Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers

Abstract

Metabolic alterations are increasingly recognized as important novel anti-cancer targets. Among several regulators of metabolic alterations, fructose 2,6 bisphosphate (F2,6BP) is a critical glycolytic regulator. Inhibition of the active form of PFKFB3 using a novel inhibitor, PFK158 resulted in reduced glucose uptake, ATP production, lactate release as well as induction of apoptosis in gynecologic cancer cells. Moreover, we found that PFK158 synergizes with carboplatin (CBPt) and paclitaxel (PTX) in the chemoresistant cell lines, C13 and HeyA8MDR but not in their chemosensitive counterparts, OV2008 and HeyA8, respectively. We determined that PFK158-induced autophagic flux leads to lipophagy resulting in the downregulation of cPLA2, a lipid droplet (LD) associated protein. Immunofluorescence and co-immunoprecipitation revealed colocalization of p62/SQSTM1 with cPLA2 in HeyA8MDR cells uncovering a novel pathway for the breakdown of LDs promoted by PFK158. Interestingly, treating the cells with the autophagic inhibitor bafilomycin A reversed the PFK158-mediated synergy and lipophagy in chemoresistant cells. Finally, in a highly metastatic PTX-resistant in vivo ovarian mouse model, a combination of PFK158 with CBPt significantly reduced tumor weight and ascites and reduced LDs in tumor tissue as seen by immunofluorescence and transmission electron microscopy compared to untreated mice. Since the majority of cancer patients will eventually recur and develop chemoresistance, our results suggest that PFK158 in combination with standard chemotherapy may have a direct clinical role in the treatment of recurrent cancer.

TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer

“…In addition to the successful use of molecules targeting metabolism in the clinic, several metabolic enzymes are evolving as potential candidate targets. Examples include but are not limited to proteins closely linked to TGFβ-induced EMT, such as GLUT1, HK2, PFKFB3, PKM2, LDHA and PDK4, proteins that control glycolysis [172][173][174][175][176][177][178][179][180], and FASN and ACC, which are involved in lipid synthesis [181][182][183][184] (Table 1). Overall, a large number of preclinical research reports provide alternative therapeutic strategies that target EMT and tumor cell migration.…”

JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms

“…However, derivatives of 3PO, such as PFK15 and PFK-158, which also inhibit PFKFB3, are now in clinical trials for treating late-stage cancer patients. 42 Increased glutamine metabolism was reported in BaF/3 cells expressing VF mutation. 43 It will be interesting to determine whether targeting glutamine metabolism alone or in combination with inhibition of glycolysis can improve therapy for MPNs.…”

PELP1/SRC-3-dependent regulation of metabolic kinases drives therapy resistant ER+ breast cancer

“…PFKFB inhibitors are emerging as promising treatments in endocrine and chemotherapy-resistant ER+ breast cancer (36). PFKFB3 inhibitor, PFK158, displays broad anti-tumor and immunomodulatory effects in human and preclinical mouse models (37) and was evaluated in a Phase I clinical trial with no significant adverse effects (38).…”