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Title: Molecular bases of Sorcin-dependent resistance to chemotherapeutic agents
Authors: Ilaria Genovese, Andrea Ilari, Theo Battista, Valerio Chiarini, Francesco Fazi, Annarita Fiorillo, Gianni Colotti
Afiliations: Italian National Research Council, Institute of Molecular Biology and Pathology; Sapienza University, Dept. Biochemical Sciences
Abstract: Sorcin (SOluble Resistance-related Calcium binding proteIN) is a protein initially labelled “resistance-related”, since it is co-amplified with ABCB1 in multidrug (MD)-resistant cells. While for years Sorcin overproduction was believed to be a by-product of the coamplification of its gene with P-glycoprotein genes, many recent reports have demonstrated that Sorcin plays a role in multidrug resistance (MDR), and pointed at a possible role as an oncoprotein. Sorcin is one of the most highly expressed calcium-binding proteins in many tissues, is overexpressed in many human tumors and MD resistant cancers, and may represent a novel marker.
The level of Sorcin expression in leukemia patients inversely correlates with patients’ response to chemotherapies and overall prognosis. In parallel, Sorcin is highly expressed in chemoresistant cell lines and significantly up-regulated in chemotherapeutic drug-induced MD resistance cell lines over their parent cells. Sorcin overexpression by gene transfection increased drug resistance to a variety of chemotherapeutic agents in many cancer lines. On the other hand, several studies have demonstrated that inhibition of Sorcin expression by RNA interference led to reversal of drug resistance in many cell lines.
This review describes: i) the roles of Sorcin in the cell; ii) the studies showing Sorcin overexpression in tumors and cancer cells; iii) the studies showing the effects of Sorcin overexpression and silencing; iv) the molecular effects of Sorcin overexpression; v) the structural and genetic bases of Sorcin-dependent MDR.
Title: Hitting a Moving Target: Inhibition Of The Nuclear Export Receptor Xpo1/Crm1 As a Therapeutic Approach In Cancer
Authors: Maria Sendino1, Miren Josu Omaetxebarria2, Jose Antonio Rodríguez1*
Afiliations: 1Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa 48940, Spain.
2Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa 48940, Spain
Abstract: Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies.
Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published.
Title: Glutamine metabolism in cancer therapy
Authors: Tra-Ly Nguyen, Raúl V. Durán
Afiliations: Institut Européen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, 2 Rue Robert Escarpit, 33607 Pessac, France
Abstract: The amino acid glutamine plays a key role in the metabolism of highly proliferating cells. During malignant transformation, cancer cells modify the consumption and processing of glutamine to sustain cell growth and proliferation. In some extreme cases, these cancer cells become addicted to glutamine. Thus, targeting the metabolism of glutamine has been developed during last years as a potential strategy against cancer. In this review, we summarized the last advances in our knowledge about the role of glutamine metabolism in cancer therapy.