fig2

Figure 2. Mechanisms of drug resistance in cancer related to ATP described in this review. eATP can be degraded to ADP, AMP by ecto-nucleotidase CD39 or sequentially to immunosuppressive adenosine by ecto-nucleotidase CD73. eATP acts as messengers outside of cancer cells through purinergic signaling including P2X receptor (P2XR, e.g., P2X7) while ADP/AMP act through P2Y receptor (P2XR, e.g., P2Y12, P2Y13) to promote cell survival signals, energy generation or/and EMT, contributing to drug resistance. eATP is also internalized by cancer cells via macropinocytosis, which results in significantly elevated iATP levels. The increased iATP molecules become more competitive against ATP analog anticancer drugs for the intracellular ATP binding domain of RTKs of GFRs on cancer cell plasma membrane, and thereby reduce RTK phosphorylation and downstream signaling involved in cell growth, proliferation and survival. Elevated iATP levels also enhance the efflux activity of ABC transporters for out-pumping anticancer drugs from cancer cells. Additionally, our recent study identified a role of iATP directly inducing EMT, and EMT confers drug resistance by numbers of mechanisms including upregulating ABC transporters. All these mechanisms work together to promote drug resistance by increasing cell survival signaling, reducing intracellular drug concentration, and inducing EMT. Further studies are needed for the final validation of ATP-mediated mechanisms of drug resistance. eATP: Intratumoral extracellular ATP; ENTPD1: ectonucleoside triphosphate diphosphohydrolase 1 (CD39); NT5E: ecto-5’-nucleotidase (CD73); EMT: epithelial-mesenchymal transition; iATP: intracellular ATP; RTK: receptor tyrosine kinase; GFR: growth factor receptor; ABC transporters: ATP-binding cassette (ABC) transporters.