Metabolic reprogramming in cancer cells: glycolysis, glutaminolysis, and Bcl-2 proteins as novel therapeutic targets for cancer

Abstract

Nearly a century ago, Otto Warburg made the ground-breaking observation that cancer cells, unlike normal cells, prefer a seemingly inefficient mechanism of glucose metabolism: aerobic glycolysis, a phenomenon now referred to as the Warburg effect. The finding that rapidly proliferating cancer cells favors incomplete metabolism of glucose, producing large amounts of lactate as opposed to synthesizing ATP to sustain cell growth, has confounded scientists for years. Further investigation into the metabolic phenotype of cancer has expanded our understanding of this puzzling conundrum, and has opened new avenues for the development of anti-cancer therapies. Enhanced glycolytic flux is now known to allow for increased synthesis of intermediates for sustaining anabolic pathways critical for cancer cell growth. Alongside the increase in glycolysis, cancer cells transform their mitochondria into synthesis machines supported by augmented glutaminolysis, supplying lipid production, amino acid synthesis, and the pentose phosphate pathways. Inhibition of several of the key enzymes involved in these pathways has been demonstrated to effectively obstruct cancer cell growth and multiplication, sensitizing them to apoptosis. The modulation of various regulatory proteins involved in metabolic processes is central to cancerous reprogramming of metabolism. The finding that members of one of the major protein families involved in cell death regulation also aberrantly regulated in cancers, the Bcl-2 family of proteins, are also critical mediators of metabolic pathways, provides strong evidence for the importance of the metabolic shift to cancer cell survival. Targeting the anti-apoptotic members of the Bcl-2 family of proteins is proving to be a successful way to selectively target cancer cells and induce apoptosis. Further understanding of how cancer cells modify metabolic regulation to increase channeling of substrates into biosynthesis will allow for the discovery of novel drug targets to treat cancer. In the present review, we focused on the recent developments in therapeutic targeting of different steps in glycolysis, glutaminolysis and on the metabolic regulatory role of Bcl-2 family proteins.

Drivers of Glucose and Glutamine Metabolism Reprogramming in Tumor Cells and Their Potential as Target for Cancer

“…The idea of interrupting the supply or utilization of the conditionally-essential amino acid glutamine in order to fight cancer dates back several decades and is based on its high concentration in plasma as well as the selective vulnerability of a variety of malignant cells to glutamine depletion [12,14,15,38].…”

“…It could be because of the form of cancer cells pyruvate kinase M2 (PKM2) that leads uncoupling of glycolysis and the Krebs's cycle as it acts as a rate limiting step in coupling the two pathways coupling of. Besides, it could also be because of inactivation of pyruvate dehydrogenase (PDH) enzyme (that is responsible for the conversion of pyruvate to acetyl CoA so as to join the Krebs's cycle) by pyruvate dehydrogenase kinases (PDK), known to be over-expressed in cancer cells [11,[12][13][14][15]. To this end, in the following sections recent findings related to the drivers of glucose and glutamine metabolism reprogramming, their crosstalk in cancer cells, and their potential as cancer therapeutic strategy will be reviewed.…”

Metabolic Reprogramming of Triple-Negative Breast Cancer: The Role of miRNAs

“…Cancerous cells use metabolic reprogramming in order to enhance biosynthesis, growth, and survival [14]. The metabolic reprogramming of cancer cells is achieved through a complex interplay of regulatory networks involving phosphatidylinositide 3-kinase (PI3K), mTOR, protein kinase B (Akt), PTEN and 5' AMP-activated protein kinase (AMPK).…”

Stretch Induces Invasive Phenotypes in Breast Cells Due to Activation of Aerobic‐Glycolysis‐Related Pathways

“…Extreme glycolytic metabolism is known to facilitate synthesis for conserve anabolic pathways for cancer cell proliferation. Through enhanced glycolysis, the mitochondria of cancer cells would be transformed into synthesis machines . Suppression in the expression of several enzymes involved in the pathways which support glycolysis (such as augmented glutaminolysis, lipid production, amino acid synthesis, and the pentose phosphate pathways)18a has been demonstrated to downregulate cancer cell growth and mitosis and induce apoptosis.…”