Cancer metabolism: current perspectives and future directions

Abstract

Cellular metabolism influences life and death decisions. An emerging theme in cancer biology is that metabolic regulation is intricately linked to cancer progression. In part, this is due to the fact that proliferation is tightly regulated by availability of nutrients. Mitogenic signals promote nutrient uptake and synthesis of DNA, RNA, proteins and lipids. Therefore, it seems straight-forward that oncogenes, that often promote proliferation, also promote metabolic changes. In this review we summarize our current understanding of how ‘metabolic transformation' is linked to oncogenic transformation, and why inhibition of metabolism may prove a cancer′s ‘Achilles' heel'. On one hand, mutation of metabolic enzymes and metabolic stress sensors confers synthetic lethality with inhibitors of metabolism. On the other hand, hyperactivation of oncogenic pathways makes tumors more susceptible to metabolic inhibition. Conversely, an adequate nutrient supply and active metabolism regulates Bcl-2 family proteins and inhibits susceptibility to apoptosis. Here, we provide an overview of the metabolic pathways that represent anti-cancer targets and the cell death pathways engaged by metabolic inhibitors. Additionally, we will detail the similarities between metabolism of cancer cells and metabolism of proliferating cells.

Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death

“…22 Glucose deprivation causes decrease of ATP, and inhibition of glycolysis induces apoptosis in cancer cells. 23 We confirm that 2-DG markedly decreased intracellular ATP concentration together with the induction of apoptosis in several cancer cell lines.…”

Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response

“…A lthough cancer represents a heterogeneous group of diseases with a wide variety of alterations, one common feature is the ability of cancer cells to use glycolysis instead of oxidative phosphorylation for their energy production (a process called the Warburg effect) (1,2). This observation has led researchers to develop new therapeutic strategies using glycolysis inhibitors such as the nonmetabolizable glucose analog 2-deoxyglucose (2DG) (3).…”

Uncovering metabolism in rhabdomyosarcoma

“…This adaptative process, known as Warburg effect, allows that glucose-derived carbon skeletons can be used for macromolecule biosynthesis rather than for complete oxidation through the tricarboxylic acid (TCA) cycle in the mitochondria. [5][6][7][8][9] As a result, cancer cells will alternatively use the glucose backbone in the pentose phosphate pathway to produce ribose for nucleotide synthesis and NADPH for lipid biosynthesis and maintainance of cell's redox status. Pushing the Warburg effect progressively triggers depletion of a-ketoacid intermediates into TCA cycle, so that cancer cells have high metabolic demands of glutamine, a non-essential amino acid precursor for a myriad of components that also serves as substrate for gluconeogenesis and as alternative energy source in rapidly dividing cells.…”