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Targeting 6‐Phosphofructo‐2‐kinase/Fructose‐2,6‐Bisphosphatase‐4 (PFKFB4) in Cancer
Author(s) -
Telang S.,
Trent J.,
Chesney J.,
Clark J.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.725.29
Subject(s) - warburg effect , cancer research , glycolysis , anaerobic glycolysis , biology , gene silencing , allosteric regulation , cell growth , kinase , cancer cell , cancer , chemistry , microbiology and biotechnology , biochemistry , receptor , enzyme , genetics , gene
High glycolytic flux, even in the presence of oxygen ( i.e. the Warburg effect), is a central neoplastic hallmark. Oncogenic activation and HIF‐1α over‐expression stimulate glycolysis by activating the 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatases (PFKFB1‐4) which synthesize fructose‐2,6‐bisphosphate (F2,6BP), a potent allosteric activator of the metabolic sensor, 6‐phosphofructo‐1‐kinase (PFK‐1). We recently found that PFKFB4 is highly expressed in multiple cancer cell types with disparate driver oncogenes, is strongly induced by hypoxia via HIF‐1α upregulation and that its suppression leads to decreased F2,6BP, glycolytic flux to lactate and the TCA cycle, increased apoptosis and inhibition of lung tumor growth in vivo . Importantly, compared with normoxia, silencing PFKFB4 in hypoxia significantly decreases survival and proliferation, indicating that PFKFB4 may be preferentially required for hypoxic survival and growth. Taken together, these data provide rationale for the development of small molecule inhibitors targeting PFKFB4. Using molecular modeling and receptor‐based virtual screening, we have identified a small molecule inhibitor of PFKFB4, termed 5MPN, that selectively inhibits recombinant PFKFB4 activity. We find that 5MPN: (i) decreases the F2,6BP, glucose uptake and proliferation of multiple cancer cells; (ii) selectively suppresses Ras‐transformed bronchial epithelial cell growth without affecting normal bronchial epithelial cells; and (iii) markedly reduces xenograft growth in vivo (IV and PO). Our data indicate that targeting PFKFB4 may be a viable therapeutic strategy against cancer and future studies will be aimed at the examination of 5MPN in combination with PFKFB3 inhibitors and other targeted anticancer agents.