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.
Highlights
Initial studies on cancer metabolism in early 20th century overlooked mitochondria in tumors, as they were deemed dysfunctional[1]
Mitochondria are central for redox balance: they are the main producers of reactive oxygen species (ROS) as respiration by-products, mitochondria modulate redox equivalents and gather the majority of enzymatic and non-enzymatic antioxidants[6]
Contrary to the traditional view, mitochondria are considered the “Achilles heel” of cancer due to the heavy dependency of cancer cells on both mitochondrial metabolism and ability to cope with stress
Summary
Initial studies on cancer metabolism in early 20th century overlooked mitochondria in tumors, as they were deemed dysfunctional[1]. The FAO inhibitors etomoxir and ranolazine activated Bak, a proapoptotic member of the Bcl-2 family, enhancing ABT-737 pro-apoptotic activity in leukemia[114] Obatoclax, another BH3 mimetic, was found to be effective in targeting chemoresistant cells, as well as increasing efficiency of chemotherapeutic drugs[115]. PGC-1α induction may confer chemoresistance by promoting a metabolic shift to overcome ATP requirements, as described for cells treated with BRAF inhibitors (Haq et al.[136] 2013) This is the case for 5FU resistance, which enhanced PGC-1α expression and altered cellular metabolism to mitigate the energetic stress induced by treatment[58,102,131]. MAPK inhibitor-resistant melanoma cells were sensitized to therapy when treated with mTORC inhibitors, which decreased PGC-1α expression and reversed metabolic changes[128]
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