Cancer Metabolism, HIF‐1, and Novel Anti‐Cancer Therapies

Increased glucose uptake and metabolism is a universal characteristic of advanced solid cancers. There are two well‐established mechanisms underlying the reprogramming of tumor metabolism. First, intratumoral hypoxia induces the activity of the transcriptional activator hypoxia‐inducible factor 1 (HIF‐1) by inhibiting the O 2 ‐dependent prolyl and asparaginyl hydroxylases that inhibit HIF‐1α stability and transactivation, respectively. Second, genetic alterations increase the activity of HIF‐1. In either case, HIF‐1 increases the expression of glucose transporters (GLUT1, GLUT3), glycolytic enzymes (ALDOA, ENO1, HK2, LDHA, PKM2), pH regulators (CAR9, NHE1, MCT4), and proteins that inhibit mitochondrial metabolism (BNIP3, PDK1). We have identified a novel feed‐forward mechanism by which PKM2 expression leads to increased HIF‐1 transcriptional activity. This pathway may be designed to increase HIF‐1 activity under non‐hypoxic conditions and may be of importance in cancers where genetic alterations increase HIF‐1α expression in an O 2 ‐independent manner. We have also demonstrated that daily administration of digoxin, acriflavine, or low‐dose doxorubicin blocks tumor growth and inhibits HIF‐1 activity by blocking HIF‐1α synthesis, HIF‐1α:HIF‐1β dimerization, and HIF‐1 DNA binding, respectively.