Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth.

Simple Summary: Cancer represents unrestricted growth with the removal of conventional brakes that control growth under normal conditions. This requires novel mechanisms to provide metabolic energy to fuel the rapid growth and also macromolecules to support cell renewal. This unique need in cancer cells is accomplished by an efficient interplay between selective nutrient transporters and the reprogramming of cellular metabolism that modifies specific catabolic and anabolic pathways. These modified biochemical pathways generate certain metabolites that are seen at high levels only in cancer cells, and reroute signaling cascades, alter gene expression profiles, and exert biological effects in support of the growth and proliferation of cancer cells. A clear understanding of the metabolic signature that is unique to cancer cells is necessary not only to appreciate how the unrestricted growth is accomplished in cancer but also to exploit these cancer-cell-specific nutrient transporters and metabolic pathways as drug targets to develop new anticancer therapeutics. Aerobic glycolysis in cancer cells, originally observed by Warburg 100 years ago, which involves the production of lactate as the end product of glucose breakdown even in the presence of adequate oxygen, is the foundation for the current interest in the cancer-cell-specific reprograming of metabolic pathways. The renewed interest in cancer cell metabolism has now gone well beyond the original Warburg effect related to glycolysis to other metabolic pathways that include amino acid metabolism, one-carbon metabolism, the pentose phosphate pathway, nucleotide synthesis, antioxidant machinery, etc. Since glucose and amino acids constitute the primary nutrients that fuel the altered metabolic pathways in cancer cells, the transporters that mediate the transfer of these nutrients and their metabolites not only across the plasma membrane but also across the mitochondrial and lysosomal membranes have become an integral component of the expansion of the Warburg effect. In this review, we focus on the interplay between these transporters and metabolic pathways that facilitates metabolic reprogramming, which has become a hallmark of cancer cells. The beneficial outcome of this recent understanding of the unique metabolic signature surrounding the Warburg effect is the identification of novel drug targets for the development of a new generation of therapeutics to treat cancer. [ABSTRACT FROM AUTHOR]