Mitochondrial determinants of chemoresistance

Ansooya Bokil, Patricia Sancho, Ansooya Bokil, Patricia Sancho

Abstract

Chemoresistance constitute nowadays the major contributor to therapy failure in most cancers. There are main factors that mitigate cell response to therapy, such as target organ, inherent sensitivity to the administered compound, its metabolism, drug efflux and influx or alterations on specific cellular targets, among others. We now know that intrinsic properties of cancer cells, including metabolic features, substantially contribute to chemoresistance. In fact, during the last years, numerous reports indicate that cancer cells resistant to chemotherapy demonstrate significant alterations in mitochondrial metabolism, membrane polarization and mass. Metabolic activity and expression of several mitochondrial proteins are modulated under treatment to cope with stress, making these organelles central players in the development of resistance to therapies. Here, we review the role of mitochondria in chemoresistant cells in terms of metabolic rewiring and function of key mitochondria-related proteins.

Keywords: ABC transporters; Mitochondria; chemoresistance; fatty acid oxidation; metabolism; oxidative phosphorylation; uncoupling proteins.

Conflict of interest statement

All authors declared that there are no conflicts of interest.

© The Author(s) 2019.

Figures

Figure 1
Figure 1
Overview of the mitochondrial determinants of resistance. Some therapeutic drugs promote a shift in metabolism. Drugs like biguanides that target the complex I of mitochondria promote a shift to glycolysis to meet ATP needs. Similarly, glutaminase inhibitors promote cells to switch to oxidative phosphorylation and BRAF protein inhibitors push cells to metabolize glutamine. Mitochondrial FAO contributes to chemoresistance to 5-fluoro-uracil (5FU), Cisplatin and Cytarabine. Increased intracellular ROS induced by enhanced expression of uncoupling proteins (UCPs), electron transport chain (ETC) activity or drug action are also responsible for chemoresistance. In addition to metabolic shifts, therapeutic drugs also elevate the expression of mitochondrial ABC transporters proteins that allow drug efflux and helps to minimize the inhibitory activity of the drug. Bcl-2 family of prosurvival proteins block apoptosis induced by chemotherapeutic drugs. Mitochondrial biogenesis is also induced during therapy-induced stress by elevation of PGC1α

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