Abstract
Cancer cells have evolved to develop sets of survival strategies to enable them not only to survive and ward off apoptosis-inducing effects of most chemotherapeutic drugs in current use but also proliferate and invade their surrounding healthy tissue. In the 1920’s, based on his pioneering research, Warburg hypothesized cancer cells rely on glycolysis for energy production to sustain their growth because their mitochondrial metabolism is dysfunctional. This review focuses on the current advances in cancer cell metabolism as a result of the recent resurgence of interests in the “Warburg hypothesis” (also called “Warburg effect”) and discusses how these advances have revealed potential anti-cancer drug targets. Additionally, we will also discuss metabolic pathways that are critically coupled to cancer cell survival and proliferation, thereby uncovering other putative anti-cancer drug targets for therapeutic consideration. Thus, we hope to provide a forward-looking framework for discussing and designing new anti-cancer therapies.
Highlights
Tumor cells have evolved to develop distinct sets of strategies to enable them to survive and ward off apoptosis-inducing effects of most chemotherapeutic drugs in current use, and to proliferate and invade their surrounding healthy tissue
This review focuses on the current advances in cancer cell metabolism as a result of the recent resurgence of interests in the “Warburg hypothesis” and discusses how these advances have revealed potential anti-cancer drug targets
This mammalian target of rapamycin (mTOR)-induced, hypoxia-inducible factor 1 (HIF-1)-mediated mechanism favors the glycolytic switch in tumor cells via the upregulation of GLUT 1 & GLUT 3, HK1 and HK2, and several other glycolytic enzymes as well as pyruvate dehydrogenase kinase 1 (PDK1), which inactivates the pyruvate dehydrogenase complex, thereby limiting the flux of glycolytically-derived pyruvate into the tricarboxylic acid (TCA) cycle [13,18,19,20]
Summary
Tumor cells have evolved to develop distinct sets of strategies to enable them to survive and ward off apoptosis-inducing effects of most chemotherapeutic drugs in current use, and to proliferate and invade their surrounding healthy tissue. In the context of the regulation of rate of HIF-1α translation in tumor cells, it is interesting to note that in many tumor types, the loss of function of tumor suppressors such as PTEN, LKB1, and/or TSC1/TSC2 due to their loss or mutations and the gain of function affecting protein tyrosine kinases, Ras and PI3K/ Akt signaling pathways contribute toward enhancing the mTOR-dependent HIF-1α translation [13,20] This mTOR-induced, HIF-1-mediated mechanism favors the glycolytic switch in tumor cells via the upregulation of GLUT 1 & GLUT 3, HK1 and HK2, and several other glycolytic enzymes as well as pyruvate dehydrogenase kinase 1 (PDK1), which inactivates the pyruvate dehydrogenase complex, thereby limiting the flux of glycolytically-derived pyruvate into the TCA cycle [13,18,19,20]. Novel sources of FASN inhibitors such as green tea and dietary soy may be further exploited for their anti-tumor and cancer prevention potentials [81]
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