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

Susmita Mondal, Debarshi Roy, Sayantani Sarkar Bhattacharya, Ling Jin, Deokbeom Jung, Song Zhang, Eleftheria Kalogera, Julie Staub, Yaxian Wang, Wen Xuyang, Ashwani Khurana, Jeremey Chien, Sucheta Telang, Jason Chesney, Gilles Tapolsky, Petras P Dzeja, Vijayalakshmi Shridhar

Research output: Contribution to journalArticle

14 Scopus citations

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 PFKFB3ser461 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.

Original languageEnglish (US)
JournalInternational Journal of Cancer
DOIs
StateAccepted/In press - Jan 1 2018

Keywords

  • Chemoresistance
  • lipid droplet
  • lipophagy
  • ovarian and cervical cancer
  • PFKFB3

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Mondal, S., Roy, D., Sarkar Bhattacharya, S., Jin, L., Jung, D., Zhang, S., Kalogera, E., Staub, J., Wang, Y., Xuyang, W., Khurana, A., Chien, J., Telang, S., Chesney, J., Tapolsky, G., Dzeja, P. P., & Shridhar, V. (Accepted/In press). Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers. International Journal of Cancer. https://doi.org/10.1002/ijc.31868