Cancer Metabolism and the Evasion of Apoptotic Cell Death

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.

Keywords: BCL-2; apoptosis; metabolism.

Figure 1

Unified model of BCL-2 protein family interactions. BH3-only activators (BIM, tBID, and PUMA) can bind to the multi-domain anti-apoptotics (BCL-2, MCL-2, BCL-x_L, BCL-w, and A1) as well as the multi-domain pro-apoptotic effectors (BAX and BAK), whereas each of the BH3-only sensitizers (NOXA, BAD, and BMF) can only bind to a subset of the multi-domain anti-apoptotics. Binding of BH3-only activator to BAX/BAK promotes the oligomerization of BAX/BAK. BAX and BAK can be inhibited by a subset of the anti-apoptotics.

Figure 2

Metabolic regulation of BCL-2 proteins inducing sensitization to BCL-2 antagonists. Glucose/glutamine deprivation can modulate the levels of BCL-2 proteins resulting in changes in binding of BH3-only proteins with the anti-apoptotic proteins. Treatment with BH3-mimetics can release activators from anti-apoptotics. Unbound/released activators then activate BAX/BAK and initiate MOMP. A subset of metabolic inhibitors (pre-clinical leads and small molecules in clinical trials) that elevate the primed state and increase sensitivity to BCL-2-targeted BH3 mimetics have been shown along with their targets. Abbreviations: 2-DG: 2-deoxyglucose; DON: 6-diazo-5-oxo-L-norleucine; AOA: aminooxyacetic acid; TTFA: thenoyl trifluoracetone.