Abstract
Cellular growth and proliferation depend upon the acquisition and synthesis of specific metabolites. These metabolites fuel the bioenergy, biosynthesis, and redox potential required for duplication of cellular biomass. Multicellular organisms maintain tissue homeostasis by balancing signals promoting proliferation and removal of cells via apoptosis. While apoptosis is in itself an energy dependent process activated by intrinsic and extrinsic signals, whether specific nutrient acquisition (elevated or suppressed) and their metabolism regulates apoptosis is less well investigated. Normal cellular metabolism is regulated by lineage specific intrinsic features and microenvironment driven extrinsic features. In the context of cancer, genetic abnormalities, unconventional microenvironments and/or therapy engage constitutive pro-survival signaling to re-program and rewire metabolism to maintain survival, growth, and proliferation. It thus becomes particularly relevant to understand whether altered nutrient acquisition and metabolism in cancer can also contribute to the evasion of apoptosis and consequently therapy resistance. Our review attempts to dissect a causal relationship between two cancer hallmarks, i.e., deregulated cellular energetics and the evasion of programmed cell death with primary focus on the intrinsic pathway of apoptosis.
Highlights
Cancer cells engage various mechanisms to evade apoptosis
We have identified that targeting glutamine metabolism increases the primed state of the cell by increasing BIM binding to BCL-2 even across MM cells that are MCL-1 dependent i.e. having BIM bound primarily to MCL-1 [119]
We have demonstrated that inhibition of succinate ubiquinone reductase (SQR) by small molecule inhibitor thenoyltrifluoroacetone (TTFA) sensitizes venetoclax-resistant MM cells [123]
Summary
Cancer cells engage various mechanisms to evade apoptosis. The intrinsic pathway of apoptosis has been shown to be frequently disrupted in cancer cells and is closely regulated by cellular metabolism. Direct evidence that metabolic changes promote resistance to therapy via alterations of BCL-2 family expression is sparse. Metabolites like glucose and glutamine have been shown to regulate the expression and binding properties of specific BCL-2 proteins. The strongest evidence that cancer metabolism regulates programmed cell death to promote resistance comes indirectly from numerous studies showing that targeting metabolism alters the apoptotic threshold sensitizing resistant cancer to various therapies. There is opportunity for developing therapies that co-target metabolic vulnerabilities and the BCL-2 family of proteins. We review the intrinsic pathway of apoptosis and its close relationship with metabolism
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