Abstract
Development of malignancy is accompanied by a complete metabolic reprogramming closely related to the acquisition of most of cancer hallmarks. In fact, key oncogenic pathways converge to adapt the metabolism of carbohydrates, proteins, lipids and nucleic acids to the dynamic tumor microenvironment, conferring a selective advantage to cancer cells. Therefore, metabolic properties of tumor cells are significantly different from those of non-transformed cells. In addition, tumor metabolic reprogramming is linked to drug resistance in cancer treatment. Accordingly, metabolic adaptations are specific vulnerabilities that can be used in different therapeutic approaches for cancer therapy. In this review, we discuss the dysregulation of the main metabolic pathways that enable cell transformation and its association with oncogenic signaling pathways, focusing on the effects of c-MYC, hypoxia inducible factor 1 (HIF1), phosphoinositide-3-kinase (PI3K), and the mechanistic target of rapamycin (mTOR) on cancer cell metabolism. Elucidating these connections is of crucial importance to identify new targets and develop selective cancer treatments that improve response to therapy and overcome the emerging resistance to chemotherapeutics.
Highlights
Multifactorial diseases are the final result of the interaction between genetic susceptibility and environmental factors in which a clear hereditary pattern is not found
In response to energy stress, Forkhead box O (FOXO) proteins inhibit the mechanistic target of rapamycin complex 1 signaling through induction of BCL2/adenovirus E1B 19kDa interacting protein 3 (BNIP3) expression, which in turn negatively regulates the mTORC1 activator RAS homolog enriched in brain (RHEB) and the BCL2 pro-survival family members, resulting in energy stress-induced apoptosis [225]
Oncogenic signals converge to reprogram tumor metabolism by enhancing key metabolic pathways such as glycolysis, phosphate pathway (PPP), glutaminolysis and amino acid, lipid and nucleic acid metabolism [19, 63]
Summary
Multifactorial diseases are the final result of the interaction between genetic susceptibility and environmental factors in which a clear hereditary pattern is not found. The enhanced glycolytic rate can be sustained through the overexpression of glucose transporters [36] and several key glycolytic www.impactjournals.com/oncotarget enzymes [37] mediated by specific activated oncogenes (e.g. PI3K and MYC) and transcription factors (e.g. HIF1), contributing to the acquisition of the Warburg effect and maintaining tumor cell growth and survival [21, 28, 33].
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