Mitochondria in colorectal cancer stem cells - a target in drug resistance
, ... Abstract
Colorectal cancer (CRC) is the third most diagnosed cancer and the second most deadly type of cancer worldwide. In late diagnosis, CRC can resist therapy regimens in which cancer stem cells (CSCs) are intimately related. CSCs are a subpopulation of tumor cells responsible for tumor initiation and maintenance, metastasis, and resistance to conventional treatments. In this scenario, colorectal cancer stem cells (CCSCs) are considered an important key for therapeutic failure and resistance. In its turn, mitochondria is an organelle involved in many mechanisms in cancer, including chemoresistance of cytotoxic drugs due to alterations in mitochondrial metabolism, apoptosis, dynamics, and mitophagy. Therefore, it is crucial to understand the mitochondrial role in CCSCs regarding CRC drug resistance. It has been shown that enhanced anti-apoptotic protein expression, mitophagy rate, and addiction to oxidative phosphorylation are the major strategies developed by CCSCs to avoid drug insults. Thus, new mitochondria-targeted drug approaches must be explored to mitigate CRC chemoresistance via the ablation of CCSCs.
Keywords
INTRODUCTION
Colorectal cancer (CRC) is the third most diagnosed cancer worldwide, the second leading cause of cancer death in women, and the third in men[1]. Currently, the chemotherapy regimens for CRC consist of
Regarding therapy resistance, researchers have sought new strategies, such as using CRC patient-derived organoids (PDOs), to understand this challenging problem. Recent studies suggest that PDOs can prevent patients from undergoing ineffective chemotherapy and can help to develop effective and personalized therapies against CRC[5,6]. However, drug resistance is still a problem to be fought, with cancer stem cells (CSCs) emerging as an important factor in the process[7]. CSCs are a subset of tumor cells defined by their ability to self-renewal and differentiate into distinct progenies, being also responsible for invasion and migration, leading to metastasis, and a slow-cycling cellular turnover, making them resistant to therapies[8,9]. CSCs have been described in many types of cancer, and colorectal cancer stem cells (CCSCs) are considered the major cause of therapeutic failure and resistance to CRC treatments, leading to tumor progression, recurrence, and, eventually, patient death[10].
The mechanisms underlying CCSCs chemoresistant phenotype include reversible quiescent state, high expression of drug efflux pumps, activation of protumoral signaling pathways, such as Hedgehog, Notch, Wnt/β-catenin, Hippo, PI3K/Akt, and TGF-β, avoidance of chemotherapeutic-induced DNA damage, dysregulation of microRNAs, hypoxia microenvironment, metabolic switch for oxidative phosphorylation (OXPHOS), among others[2].
Since conventional anticancer therapies act on highly proliferating cells, it does not affect quiescent cancer stem cells, as they are restrained in the G0 phase from the cell cycle, a non-proliferative state. Additionally, these cells can re-enter the cell cycle after undergoing chemotherapy, leading to cell proliferation and tumor regeneration[11]. Francescangeli et al.[12] showed a high proportion of quiescent and chemoresistant CCSCs in response to treatment with oxaliplatin and 5-fluorouracil in a xenograft model.
Several studies have shown that mitochondria are involved in the mechanisms of chemoresistance of cytotoxic drugs or radiotherapy due to the many metabolic pathways conferring tumor cells’ resistant phenotype and, specifically, CSCs[13-15]. Therefore, it is important to understand the mitochondrial role in CRC drug resistance mediated by cancer stem cells.
MITOCHONDRIAL ROLE IN DRUG RESISTANCE: AN OVERVIEW
Beyond the powerhouse of the cell, mitochondria have been shown to act in many different frontlines, such as cell survival, proliferation, autophagy, and calcium homeostasis[16]. In cancer, these double-membrane organelles play a pivotal role in establishing and progressing the disease, ranging from mitochondrial dynamics, biogenesis metabolism, and cell death regulation. Reactive oxygen species (ROS) balance mitochondria DNA (mtDNA) mutations[17], drug resistance, and mitochondria work like stress sensors, mediating adaptations in the face of an adverse environment caused by chemo or radiotherapies[18,19].
Some major mechanisms for drug resistance include alterations in drug transport and metabolism, enhanced DNA damage repair machinery, and inhibition of apoptosis[20]. Most chemoresistant tumors present a high expression of drug efflux membrane transporters, wherein the ATP-binding cassette (ABC) transporter family is the most important, highlighting ABCB1 and ABCG2, which are key players in cancer chemoresistance as they are capable of transporting the majority of conventional chemotherapeutic agents[21] Since ABC transporters depend on ATP hydrolysis to pump chemotherapeutics, mitochondria have their importance heightened as they are major producers of ATP via OXPHOS. A recent study using chemoresistant ovarian cancer cells showed that electron transport chain inhibitors increased drug retention and reverted the chemoresistant phenotype in vitro and in vivo[22].
Mitochondria morphology is also an important feature of drug resistance. It is a dynamic organelle and can vary in size and copies inside cells due to fusion and fission, which are regulated by a GTPase family of proteins. Mitochondrial fusion, which usually occurs in nutrient deprivation and increased OXPHOS cases, implicates long interconnected tubules, forming networks. Oppositely, mitochondrial fission appears as small and fragmented mitochondria, commonly associated with cellular and mitochondrial dysfunction, severe stress, and increased proliferation[23]. A study using cisplatin-resistant cervical and ovarian cancer cell lines exhibited a prevalence of elongated mitochondria, similar to tubular shapes, suggesting that mitochondria fusion is required to resist the drug treatment[24]. Nevertheless, studies in breast cancer and acute lymphoblastic leukemia cellular lineages have demonstrated that mitochondria fission is required for metabolic adaptation favorable for protecting cells from chemotherapy agents[25,26]. In addition, mitochondrial fission factor (MFF) is upregulated in prostate cancer stem cells compared to the primary tumor and normal prostate cells[27]. A novel study with metastatic breast cancer cells shows that changes in mitochondrial dynamics, tending to a fission increase, lead to increased production of mitochondrial ROS, which retrograde response endows cells with resistance to oxidative stress and reactive oxygen species-dependent chemotherapy drugs[28]. Therefore, the role of mitochondrial dynamics on drug resistance is an important area for further study.
Considering that mitochondria act as a metabolic hub, these organelles are expected to have great importance in modulating therapy sensitivity, especially by controlling redox metabolism[29]. Resistant cancer cells usually exhibit great mitochondrial functionality, with high rates of OXPHOS. For instance, many studies have shown that OXPHOS inhibitors suppress resistance to anticancer drugs in lung adenocarcinoma, prostate cancer, melanoma, pancreatic cancer, and colon cancer[30]. A study showed that treating ovarian cancer cells with cisplatin might induce oxidative phosphorylation and stem cell enrichment, which can be overcome using OXPHOS inhibitors[31]. Fatty acids oxidation (FAO), which depends on mitochondrial enzymes, is also considered an accomplice of therapeutic resistance[32], as a study demonstrated that FAO inhibition promotes chemosensitivity in breast CSCs[33]. Lee et al.[34] showed that liver cancer stems cell chemoresistance depends on glutamine metabolism by mitochondria since mitochondrial ATP used in drug efflux is provided by glutamine, and its inhibition reduces efflux, decreasing chemoresistance. Increased expression of MTHFD2, a mitochondrial enzyme involved in the one-carbon metabolic pathway, was observed in gefitinib-resistant lung cancer cells with stem cell features. MTHFD2 knockdown decreased stem cell phenotype and promoted gefitinib sensitization, highlighting the MTHFD2 importance and potential as a target for anticancer therapy[35]. Another important pathway in which mitochondria participate in is folate metabolism, also known as 1C metabolism[36]. This metabolic process involves the activation and transference of one carbon-molecules to support nitrogenous bases biosynthesis, antioxidant agents’ regeneration, and amino acid balance. In this scenario, mitochondria can be responsible for chemoresistance fueling 1C metabolism, then enhancing OXPHOS. Lucas et al.[37] observed that the activity of SHMT2, a mitochondrial enzyme involved in serine and tetrahydrofolate metabolism, ensures complex I assembly and function, thus increasing the electron transport chain activity and developing resistance.
Resistance to apoptosis is described as one hallmark of cancer, and its contribution to resistant cancer cells is remarkably relevant[38]. Indeed, the correct functioning of mitochondria is fundamental for cellular health. It also has an essential role in programmed cell death, and its morphology is critically important for apoptosis commitment[39]. Changes in the permeability of the inner mitochondrial membrane lead to the loss of the mitochondrial membrane potential allowing the release of pro-apoptotic proteins, such as B-cell lymphoma 2 (Bcl-2) family proteins (Bcl-2, Bcl-xl, Bcl-W, MCL-1, A1, and Bcl-B)[40,41]. Xu et al.[42] showed that overexpression of Bcl-2 blocked apoptosis in human ovarian cancer cells. In addition, other pro-apoptotic proteins, such as apoptosis-inducing factor (AIF) and endonuclease G (Endo G), are released from a late event in apoptosis, which occurs once the cells are committed to dying[40]. AIF and Endo G act in a caspase-independent manner to execute cell death[43]. Alvero et al.[44] were shown that Endo G mediates caspase-independent cell death in response to chemotherapeutic agents in an ovarian cancer model. One of the aims of chemotherapy is to induce apoptosis by targeting these pro-apoptotic proteins, mainly the Bcl-2 family, creating mitochondrial outer membrane permeabilization, which results in the irreversible release of cytochrome c, caspase activation and then apoptosis[45]. For instance, docetaxel, a common chemotherapeutic agent whose primary mechanism of action is inhibition of microtubule disassembly, can also bind to Bcl-2, inducing apoptosis[46]. Furthermore, a cutting-edge contribution of mitochondria in cancer drug resistance is the exchange of this organelle mediated by tunneling nanotubes, a transient cytoplasmic connection between non-adjacent cells[47]. Several studies have described mitochondrial transfer from important stromal cells of the tumor microenvironment, such as endothelial cells and mesenchymal stem cells, to cancer cells in many types of cancer, such as breast cancer[48], acute myeloid leukemia[49] and glioblastoma[50]. This mechanism promotes tumor survival and chemoresistance by improving OXPHOS or increasing anti-apoptotic proteins.
Mitochondria-targeted drugs for cancer - current status
Since mitochondria are a central organelle for cell survival, including cancer cells, several researchers have dedicated time and effort in recent years to develop new anticancer drugs and strategies that could target mitochondria. This group of compounds, proposed to impair mitochondria, are designated as mitochondria-targeted drugs (MTDs). Their mechanism of action can range from targeting tricarboxylic (TCA) cycle enzymes to electron transport chain (ETC) complexes and Bcl-2 anti-apoptotic family proteins[51]. Some MTDs studied comprise Mito-carboxy proxyl (Mito-CP), Mito-metformin, and Mito-methyl coumarin.
Mito-CP, a lipophilic cationic nitroxide conjugated to an alkyl triphenylphosphonium cation (TPP), showed to accumulate in mitochondria, combined with 2-deoxyglucose (2-DG), a glycolysis inhibitor, in hepatocellular carcinoma and breast cancer cells, inducing apoptosis via caspase 3/7 activation and a significant decrease in intracellular ATP. Notwithstanding, Mito-CP did not affect primary hepatocytes cells or non-tumoral fibrocystic breast cell line (MCF10A), highlighting a possible selectivity of this compound[52,53]. Concerning colorectal cancer, Boyle et al.[54] demonstrated for the first time that MTDs induce mitophagy in cancer cells. In the study, Mito-CP and Mito-Metformin, a TPP-conjugated derivative of a common type 2 diabetes drug metformin which acts inhibiting complex I of mitochondrial respiratory chain, released Unc-51-like autophagy-activating kinase 1 (ULK1) from mTOR-mediated inhibition, affecting mitochondrial morphology, and decreasing mitochondrial membrane potential, which are indicators of mitophagy. Another MTDs is Mito-methyl coumarin, a compound synthesized using the coumarin backbone, which exhibited anticancer proprieties in Hela cells by increasing ROS generation, reducing mitochondrial mass and membrane potential, and inducing programmed cell death[55].
Regarding cancer chemotherapy resistance, Chan et al.[56] showed that drug molecules carried by multifunctional nanodiamonds could be effectively delivered to mitochondria and induce remarkable cytotoxicity and cell death in doxorubicin-resistant MCF-7 breast cancer cells. In addition, Li et al.[57] synthesized mitochondria-targeted polydopamine nanoparticles loaded with doxorubicin and demonstrated that this system could potentially overcome drug resistance with a short-term treatment plan toward breast cancer cell lines (MDA-MB-231).
Focusing on cancer stem cells (CSCs), MTDs are considerably more effective in triggering apoptosis of CSCs, when compared to other agents, via mitochondrial dysfunction by regulating Bcl-2 family proteins, and ROS production[58]. Thus, specific mitochondrial-targeted compounds can induce cell death in chemoresistant CSCs. For example, Hirsch et al.[59] showed that metformin, an inhibitor of the complex I mitochondrial respiratory chain, selectively kills CSCs in breast cancer cell lines. Alvero et al.[60] demonstrated that the novel isoflavone derivative NV-128 significantly decreased mitochondrial function and induced cell death in ovarian CSCs.
Although only one MTD has been approved for cancer treatment (BH3 mimetic Venetoclax) so far, other drugs have shown beneficial and promising effects in phase I/Ib and phase I clinical trials, such as MitoTam (EudraCT 2017-004441-25)[61] and IACS-01075917 (NCT03291938)[62], respectively. Given the importance of mitochondria for cancer cells, especially cancer stem cells, further research on agents that target mitochondria and combining these drugs with other chemotherapeutics are encouraged to increase the efficiency of anticancer therapies.
CANCER STEM CELLS AND MITOCHONDRIA: A STRONG PAIR IN DRUG RESISTANCE IN CRC
As already described, mitochondria are involved in many metabolic pathways, and alterations in this metabolism have been found in CSCs[24]. Huang et al.[63] discovered that suppressing mitochondrial ROS production drives glioma stem-like cell progression and facilitates radiotherapeutic resistance. In addition, Ren et al.[64]. observed alterations in mitochondrial function, such as the low amount of mtDNA and oxygen/glucose consumption and low intracellular ROS and ATP concentrations in thyroid cancer stem cells, which contribute to radioresistance. Kuntz et al.[65] indicate that alterations in essential mitochondrial functions, such as oxidative phosphorylation, contribute to therapy-resistant chronic myeloid leukemia stem cells.
The damage of mtDNA, or even its loss, causes a reduction in the proliferation rate of CSCs[27]. Huang et al.[66] show that mtDNA deficiency may induce ovarian cancer stem cell-like properties and reveal the downregulation of mitochondria-related genes and upregulation of genes related to cell proliferation, anti-apoptosis, and drug resistance. Although these data indicate mitochondrial dysfunction and OXPHOS reduction, it has been reported the coexistence of a CSCs subpopulation that produces ATP via an anaerobic glycolytic pathway and feeds the OXPHOS of the OXPHOS-addicted subpopulation. This metabolic shift, known as the Warburg effect, usually occurs in regions of tumor hypoxia[67]. Genetic and epigenetic alterations were found in the mtDNA of cisplatin-resistant oral squamous cancer cells. Further study of these changes may help to elucidate their role in chemoresistance[68].
Concerning apoptosis, CSCs survival depends on the dysregulation of apoptosis pathways and the overexpression of anti-apoptotic proteins[69]. The anti-apoptotic proteins include the cellular FLICE-inhibitory protein (c-FLIP), the Bcl-2 family of proteins, and the inhibitor of apoptosis proteins (IAPs). Piggott et al.[70] showed that the overexpression of c-FLIP plays a crucial role in resistance to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, an anticancer agent, in breast cancer stem cells. Guo et al.[71] indicated that survivin/BRIC5, a member of the IAPs family, is promising to be an excellent candidate for recombinant anti-cancer protein by promoting apoptosis of cancer cells and their stem cells through sensitizing cells to chemotherapeutic drugs.
Furthermore, CSCs and mitochondrial dynamics are valuable partners for overcoming drug resistance[72]. Brain CSCs derived from tumor xenografts and primary tumor samples showed higher fragmented mitochondria and activation phosphorylation of dynamin-related protein 1 (DRP1) compared to non-CSCs[73]. Notwithstanding, in a breast cancer model, mitochondrial fusion promoted by upregulation of MCL-1 showed to maintain CSCs properties in cooperation with MYC, facilitating mitochondrial respiration, thus inducing chemotherapy resistance[74].
Apoptotic proteins expression
In CRC, there is an intimate relationship between CSCs and mitochondria in drug resistance scope [Figure 1]. Regarding the apoptosis mitochondrial pathway, recent data ensure that anti-apoptotic protein overexpression is vital for CCSCs chemoresistance. Purushothaman et al.[75] showed that untreated CD133+ CCSCs (HCT116) expressed lower Bax/Bak oligomerization and higher Bcl-2 in comparison to Ruthenium(II) complex 1-treated group. In agreement with these findings, Colak et al.[76] observed that CCSCs have decreased mitochondrial priming, accumulating anti-apoptotic proteins and inducing chemoresistance instead of differentiated CRC cells. In contrast, CCSCs incubated with WEHI-539, a specific inhibitor of Bcl-xl, were more sensitive to oxaliplatin, indicating that the mitochondrial apoptosis pathway is a great potential target for drug-resistant CCSCs. Ramesh et al.[77] demonstrated that treatment with a BCL-XL inhibitor (A-1155463) increased the percentage of cells with active caspase-3 in Wnt-high CCSCs, indicating cell death, while BCL-2 (ABT-199) and MCL-1 (AZD5991) inhibitors did not promote this effect. These data suggest that CCSCs may depend only on BCL-XL and not on BCL-2 and MCL-1, indicating the therapeutic potential of inhibiting BCL-XL activity.
Figure 1. Mitochondria involvement in colorectal cancer stem cells and drug resistance. (1) Reduced apoptosis due to lower Bax/Bak oligomerization and higher Bcl-2 expression. (2) Enhanced mitophagy with the participation of RAB7 and higher BNIP3L expression. (3) Addiction to OXPHOS with high mitochondrial membrane potential. The vectors used in the figure are from BioRender©. BNIP3L: BCL2 Interacting Protein 3 Like; CCSCs: colorectal cancer stem cells; OXPHOS: oxidative phosphorylation; RAB7: Ras-related protein 7.
Mitophagy rates
Mitophagy has also been assessed in CCSCs as it is another important mechanism for therapy resistance in cancer. Takeda et al.[78] demonstrated that mitophagy was enhanced among CCSCs compared to non-CCSCs, and the knockdown of RAS-Associated proteins (RAB5 and RAB7) diminished the CD44v9+/CD133+ CCSCs population. Yan et al.[79] showed that CD44+/CD133+ CCSCs (HCT8 cell lineage) were more resistant to doxorubicin treatment and expressed higher levels of BNIP3L, a mitophagy-related protein concerning parental cells. Instead, when CCSCs were treated with siRNA for BNIP3L, they became more sensitive to doxorubicin, suggesting that mitophagy is a major strategy of CCSCs to escape from death.
Oxidative phosphorylation addiction
Regarding metabolism, Denise et al.[80] showed that 5-FU resistant colorectal HT29 cancer cells are addicted to OXPHOS while expressing more CD133 and forming more spheres, a 3D cell culture, in vitro. The coadministration of 5-FU and respiratory chain complex inhibitors led to a shrinkage of spheres. Corroborating to these findings, Song et al.[81] demonstrated that CD133+/CD44+/Lgr5+ CCSCs were highly dependent on OXPHOS and presented high mitochondrial membrane potential. Besides, it was observed that the incubation with 5-FU did not alter ATP levels of CD133+ CCSCs compared to non-CCSCs. Combinate treatment of 5-FU and antimycin A, an inhibitor of complex III from the respiratory chain, promoted cell death along with high expression of cleaved caspase 3. Thus, the addiction to OXPHOS appears to support CCSCs phenotype.
CONCLUSION
Colorectal cancer remains a disease of great concern as therapy resistance remains a remarkable challenge. In this scenario, cancer stem cells are well-known contributors, and their mitochondria exhibited a valuable role in providing it. A major mechanism for chemotherapeutic avoidance in CRC is an enhancement in anti-apoptotic protein expression among CSCs, a higher mitophagy rate and a reliance on OXPHOS.
In this concern, studies involving approaches such as patient-derived xenografts and organoids should be conducted to expand the understanding of the correlation of CCSCs and their mitochondria, regarding energetic metabolism, apoptosis pathway, especially mitophagy, providing a better picture of the heterogeneity intrinsic to CRC and its chemoresistance. The literature also lacks studies about mitochondria morphology in CCSCs in drug resistance context, which is a potential topic for new remarks. Moreover, new chemotherapy strategies targeting mitochondria must be studied and developed aiming at the elimination of CCSCs and their great contribution to CRC chemotherapy resistance.
DECLARATIONS
AcknowledgmentsThe authors are grateful for Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
Authors’ contributionConceptualization: Rainho MA
Literature search, data analysis, and manuscript draft: Rainho MA, Siqueira PB, de Amorim ÍSS
Critical revision: Thole AA, Mencalha AL
Availability of data and materialsNot applicable.
Financial support and sponsorshipThis work was supported by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Grant numbers (Mencalha AL): 200.318/2023/FAPERJ; 302095/2022-5/CNPq.
Conflicts of interestAll authors declared that there are no conflicts of interest.
Ethical approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Copyright© The Author(s) 2023.
REFERENCES
1. Azwar S, Seow HF, Abdullah M, Faisal Jabar M, Mohtarrudin N. Recent updates on mechanisms of resistance to 5-fluorouracil and reversal strategies in colon cancer treatment. Biology 2021;10:854.
2. Das PK, Islam F, Lam AK. The roles of cancer stem cells and therapy resistance in colorectal Carcinoma. Cells 2020;9:1392.
3. Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of lynch syndrome pan-cancer. J Clin Oncol 2019;37:286-95.
4. Luo XJ, Zhao Q, Liu J, et al. Novel genetic and epigenetic biomarkers of prognostic and predictive significance in stage II/III colorectal cancer. Mol Ther 2021;29:587-96.
5. Papaccio F, García-Mico B, Gimeno-Valiente F, et al. “Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction”. J Exp Clin Cancer Res 2023;42:8.
6. Ooft SN, Weeber F, Dijkstra KK, et al. Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients. Sci Transl Med 2019;11:eaay2574.
7. Najafi M, Mortezaee K, Majidpoor J. Cancer stem cell (CSC) resistance drivers. Life Sci 2019;234:116781.
10. Hervieu C, Christou N, Battu S, Mathonnet M. The role of cancer stem cells in colorectal cancer: from the basics to novel clinical trials. Cancers 2021;13:1092.
11. Lee SH, Reed-Newman T, Anant S, Ramasamy TS. Regulatory role of quiescence in the biological function of cancer stem cells. Stem Cell Rev Rep 2020;16:1185-207.
12. Francescangeli F, Contavalli P, De Angelis ML, et al. A pre-existing population of ZEB2+ quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer. J Exp Clin Cancer Res 2020;39:2.
13. Cannino G, Ciscato F, Masgras I, Sánchez-Martín C, Rasola A. Metabolic plasticity of tumor cell mitochondria. Front Oncol 2018;8:333.
14. Jagust P, de Luxán-Delgado B, Parejo-Alonso B, Sancho P. Metabolism-based therapeutic strategies targeting cancer stem cells. Front Pharmacol 2019;10:203.
15. Shin MK, Cheong JH. Mitochondria-centric bioenergetic characteristics in cancer stem-like cells. Arch Pharm Res 2019;42:113-27.
18. Bokil A, Sancho P. Mitochondrial determinants of chemoresistance. Cancer Drug Resist 2019;2:634-46.
19. Jin P, Jiang J, Zhou L, et al. Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management. J Hematol Oncol 2022;15:97.
20. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 2013;13:714-26.
21. Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer 2018;18:452-64.
22. Giddings EL, Champagne DP, Wu MH, et al. Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance. Nat Commun 2021;12:2804.
23. Maycotte P, Marín-Hernández A, Goyri-Aguirre M, Anaya-Ruiz M, Reyes-Leyva J, Cortés-Hernández P. Mitochondrial dynamics and cancer. Tumour Biol 2017;39:1010428317698391.
24. Kong B, Wang Q, Fung E, Xue K, Tsang BK. p53 is required for cisplatin-induced processing of the mitochondrial fusion protein L-Opa1 that is mediated by the mitochondrial metallopeptidase Oma1 in gynecologic cancers. J Biol Chem 2014;289:27134-45.
25. Tomková V, Sandoval-Acuña C, Torrealba N, Truksa J. Mitochondrial fragmentation, elevated mitochondrial superoxide and respiratory supercomplexes disassembly is connected with the tamoxifen-resistant phenotype of breast cancer cells. Free Radic Biol Med 2019;143:510-21.
26. Cai J, Wang J, Huang Y, et al. ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells. Cell Death Dis 2016;7:e2459.
27. Civenni G, Bosotti R, Timpanaro A, et al. Epigenetic control of mitochondrial fission enables self-renewal of stem-like tumor cells in human prostate cancer. Cell Metab 2019;30:303-318.e6.
28. Romani P, Nirchio N, Arboit M, et al. Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance. Nat Cell Biol 2022;24:168-80.
29. Li J, Eu JQ, Kong LR, et al. Targeting metabolism in cancer cells and the tumour microenvironment for cancer therapy. Molecules 2020;25:4831.
30. Sica V, Bravo-San Pedro JM, Stoll G, Kroemer G. Oxidative phosphorylation as a potential therapeutic target for cancer therapy. Int J Cancer 2020;146:10-7.
31. Sriramkumar S, Sood R, Huntington TD, et al. Platinum-induced mitochondrial OXPHOS contributes to cancer stem cell enrichment in ovarian cancer. J Transl Med 2022;20:246.
32. Yi M, Li J, Chen S, et al. Emerging role of lipid metabolism alterations in cancer stem cells. J Exp Clin Cancer Res 2018;37:118.
33. Wang T, Fahrmann JF, Lee H, et al. JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab 2018;27:136-150.e5.
34. Lee ACK, Lau PM, Kwan YW, Kong SK. Mitochondrial fuel dependence on glutamine drives chemo-resistance in the cancer stem cells of hepatocellular carcinoma. Int J Mol Sci 2021;22:3315.
35. Nishimura T, Nakata A, Chen X, et al. Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2. Oncogene 2019;38:2464-81.
36. Franczak M, Toenshoff I, Jansen G, Smolenski RT, Giovannetti E, Peters GJ. The influence of mitochondrial energy and 1C metabolism on the efficacy of anticancer drugs: exploring potential mechanisms of resistance. Curr Med Chem 2023;30:1209-31.
37. Lucas S, Chen G, Aras S, Wang J. Serine catabolism is essential to maintain mitochondrial respiration in mammalian cells. Life Sci Alliance 2018;1:e201800036.
39. Abate M, Festa A, Falco M, et al. Mitochondria as playmakers of apoptosis, autophagy and senescence. Semin Cell Dev Biol 2020;98:139-53.
40. Indran IR, Tufo G, Pervaiz S, Brenner C. Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochim Biophys Acta 2011;1807:735-45.
41. Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol 2019;20:175-93.
42. Xu L, Xie Q, Qi L, et al. Bcl-2 overexpression reduces cisplatin cytotoxicity by decreasing ER-mitochondrial Ca2+ signaling in SKOV3 cells. Oncol Rep 2018;39:985-92.
43. Joza N, Susin SA, Daugas E, et al. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 2001;410:549-54.
44. Alvero AB, Montagna MK, Chen R, et al. NV-128, a novel isoflavone derivative, induces caspase-independent cell death through the Akt/mammalian target of rapamycin pathway. Cancer 2009;115:3204-16.
45. Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 2010;11:621-32.
46. Ioannidou E, et al. Angiogenesis and anti-angiogenic treatment in prostate cancer: mechanisms of action and molecular targets. Int J Mol Sci 2021;22:9926.
47. Hekmatshoar Y, Nakhle J, Galloni M, Vignais ML. The role of metabolism and tunneling nanotube-mediated intercellular mitochondria exchange in cancer drug resistance. Biochem J 2018;475:2305-28.
48. Caicedo A, Fritz V, Brondello JM, et al. MitoCeption as a new tool to assess the effects of mesenchymal stem/stromal cell mitochondria on cancer cell metabolism and function. Sci Rep 2015;5:9073.
49. Moschoi R, Imbert V, Nebout M, et al. Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood 2016;128:253-64.
50. Nzigou Mombo B, Gerbal-Chaloin S, Bokus A, et al. Mitoception: transferring isolated human MSC mitochondria to glioblastoma stem cells. J Vis Exp 2017; doi: 10.3791/55245-v.
51. Fialova JL, Raudenska M, Jakubek M, et al. Novel mitochondria-targeted drugs for cancer therapy. Mini Rev Med Chem 2021;21:816-32.
52. Dilip A, Cheng G, Joseph J, et al. Mitochondria-targeted antioxidant and glycolysis inhibition: synergistic therapy in hepatocellular carcinoma. Anticancer Drug 2013;24:881-8.
53. Cheng G, Zielonka J, Dranka BP, et al. Mitochondria-targeted drugs synergize with 2-deoxyglucose to trigger breast cancer cell death. Cancer Res 2012;72:2634-44.
54. Boyle KA, Van Wickle J, Hill RB, Marchese A, Kalyanaraman B, Dwinell MB. Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation. J Biol Chem 2018;293:14891-904.
55. Wang H, Xu W. Mito-methyl coumarin, a novel mitochondria-targeted drug with great antitumor potential was synthesized. Biochem Biophys Res Commun 2017;489:1-7.
56. Chan MS, Liu LS, Leung HM, Lo PK. Cancer-cell-specific mitochondria-targeted drug delivery by dual-ligand-functionalized nanodiamonds circumvent drug resistance. ACS Appl Mater Interf 2017;9:11780-9.
57. Li WQ, Wang Z, Hao S, et al. Mitochondria-targeting polydopamine nanoparticles to deliver doxorubicin for overcoming drug resistance. ACS Appl Mater Interf 2017;9:16793-802.
58. Song IS, Jeong JY, Jeong SH, et al. Mitochondria as therapeutic targets for cancer stem cells. World J Stem Cells 2015;7:418-27.
59. Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci U S A 2013;110:972-7.
60. Alvero AB, Montagna MK, Holmberg JC, Craveiro V, Brown D, Mor G. Targeting the mitochondria activates two independent cell death pathways in ovarian cancer stem cells. Mol Cancer Ther 2011;10:1385-93.
61. Bielcikova Z, Stursa J, Krizova L, et al. Mitochondrially targeted tamoxifen in patients with metastatic solid tumours: an open-label, phase I/Ib single-centre trial. EClinicalMedicine 2023;57:101873.
62. Yap TA, Rodon Ahnert J, Piha-paul SA, et al. Phase I trial of IACS-010759 (IACS), a potent, selective inhibitor of complex I of the mitochondrial electron transport chain, in patients (pts) with advanced solid tumors. JCO 2019;37:3014-3014.
63. Huang H, Zhang S, Li Y, et al. Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance. Nat Commun 2021;12:3720.
64. Ren Y, Liang H, Wang X, Cao Z, Ma Y, Liu X. Alterations in mitochondrial function and energy metabolism-related properties in thyroid cancer stem cells. Acta Biochim Pol 2021;69:11-7.
65. Kuntz EM, Baquero P, Michie AM, et al. Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nat Med 2017;23:1234-40.
66. Huang R, Wang J, Zhong Y, et al. Mitochondrial DNA deficiency in ovarian cancer cells and cancer stem cell-like properties. Available from: https://ar.iiarjournals.org/content/anticanres/35/7/3743.full.pdf [Last accessed on 5 May 2023].
67. Lai HT, Chiang CT, Tseng WK, Chao TC, Su Y. GATA6 enhances the stemness of human colon cancer cells by creating a metabolic symbiosis through upregulating LRH-1 expression. Mol Oncol 2020;14:1327-47.
68. Aminuddin A, Ng PY, Leong CO, Chua EW. Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma. Sci Rep 2020;10:7885.
69. Safa AR. Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces. Cancer Drug Resist 2022;5:850-72.
70. Piggott L, Omidvar N, Martí Pérez S, French R, Eberl M, Clarkson RW. Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL. Breast Cancer Res 2011;13:R88.
71. Guo W, Ma X, Fu Y, et al. Discovering and characterizing of survivin dominant negative mutants with stronger pro-apoptotic activity on cancer cells and CSCs. Front Oncol 2021;11:635233.
72. Sessions DT, Kashatus DF. Mitochondrial dynamics in cancer stem cells. Cell Mol Life Sci 2021;78:3803-16.
73. Xie Q, Wu Q, Horbinski CM, et al. Mitochondrial control by DRP1 in brain tumor initiating cells. Nat Neurosci 2015;18:501-10.
74. Lee KM, Giltnane JM, Balko JM, et al. MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab 2017;26:633-647.e7.
75. Purushothaman B, Arumugam P, Ju H, Kulsi G, Samson AAS, Song JM. Novel ruthenium(II) triazine complex [Ru(bdpta)(tpy)]2+ co-targeting drug resistant GRP78 and subcellular organelles in cancer stem cells. Eur J Med Chem 2018;156:747-59.
76. Colak S, Zimberlin CD, Fessler E, et al. Decreased mitochondrial priming determines chemoresistance of colon cancer stem cells. Cell Death Differ 2014;21:1170-7.
77. Ramesh P, Lannagan TRM, Jackstadt R, et al. BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer. Cell Death Differ 2021;28:3282-96.
78. Takeda M, Koseki J, Takahashi H, et al. Disruption of endolysosomal RAB5/7 efficiently eliminates colorectal cancer stem cells. Cancer Res 2019;79:1426-37.
79. Yan C, Luo L, Guo CY, et al. Doxorubicin-induced mitophagy contributes to drug resistance in cancer stem cells from HCT8 human colorectal cancer cells. Cancer Lett 2017;388:34-42.
80. Denise C, Paoli P, Calvani M, et al. 5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits. Oncotarget 2015;6:41706-21.
Cite This Article
Export citation file: BibTeX | RIS
OAE Style
Rainho MA, Siqueira PB, de Amorim SS, Mencalha AL, Thole AA. Mitochondria in colorectal cancer stem cells - a target in drug resistance. Cancer Drug Resist 2023;6:273-83. http://dx.doi.org/10.20517/cdr.2022.116
AMA Style
Rainho MA, Siqueira PB, de Amorim SS, Mencalha AL, Thole AA. Mitochondria in colorectal cancer stem cells - a target in drug resistance. Cancer Drug Resistance. 2023; 6(2): 273-83. http://dx.doi.org/10.20517/cdr.2022.116
Chicago/Turabian Style
Rainho, Mateus de Almeida, Priscyanne Barreto Siqueira, Ísis Salviano Soares de Amorim, Andre Luiz Mencalha, Alessandra Alves Thole. 2023. "Mitochondria in colorectal cancer stem cells - a target in drug resistance" Cancer Drug Resistance. 6, no.2: 273-83. http://dx.doi.org/10.20517/cdr.2022.116
ACS Style
Rainho, MA.; Siqueira PB.; de Amorim SS.; Mencalha AL.; Thole AA. Mitochondria in colorectal cancer stem cells - a target in drug resistance. Cancer Drug Resist. 2023, 6, 273-83. http://dx.doi.org/10.20517/cdr.2022.116
About This Article
Copyright
Data & Comments
Data
Cite This Article 28 clicks
Like This Article 17
likes
Comments
Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at support@oaepublish.com.