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.

mTOR Regulation of Metabolism in Hematologic Malignancies

“…We have learned from the literature that alterations in cellular metabolism pathways are manifest in cancer cells as compared to normal tissue cells [39][40][41].…”

Lithium chloride increases sensitivity to photon irradiation treatment in primary mesenchymal colon cancer cells

“…it has been suggested that high levels of these eMT-TFs can also cause resistance to apoptosis by altering the TGF-β-and p53-mediated programmed cell death pathways (21)(22)(23)(24). Apoptosis is an energy-dependent mechanism of programmed cell death by which organisms maintain tissue homeostasis (25). Several pathways regulate apoptosis and several mechanisms are used by tumor cells to survive, suppressing apoptotic program.…”

“…The intrinsic pathway is altered in most cancer cells and is closely regulated by cellular metabolism. indeed metabolic changes occurring in cancer cells, consequent to oncogenic activation or stress-induced therapy, promote resistance to apoptosis and therapy via alterations of Bcl-2 family expression (25). P53, a protein often altered in tumor progression, has been implicated in the activation of the intrinsic and extrinsic pathways, and its ability to induce apoptosis depends on nF-κB activation (30).…”

Isoliquiritigenin inhibits the proliferation, migration and metastasis of Hep3B cells via suppressing cyclin D1 and PI3K/AKT pathway

“…The capability of sustained uncontrollable proliferation is a major feature of cancer cells. This feature is closely related to abnormalities of cell cycle regulation and mechanisms of apoptosis resistance [12][13][14]. Inhibiting the transition of cell cycle and inducing apoptosis of tumor cells have become a mature strategy and research direction for anti-tumor therapy, especially in HCC treatment [12,15,16].…”