Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers
العنوان: | Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers |
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المؤلفون: | Yaxian Wang, Wen Xuyang, Sucheta Telang, Julie Staub, Ling Jin, Debarshi Roy, Dzeja Petras, Gilles Tapolsky, Jeremey Chien, Sayantani Sarkar Bhattacharya, Ashwani Khurana, Deok-Beom Jung, Viji Shridhar, Jason Chesney, Eleftheria Kalogera, Song Zhang, Susmita Mondal |
المصدر: | International Journal of Cancer. 144:178-189 |
بيانات النشر: | Wiley, 2018. |
سنة النشر: | 2018 |
مصطلحات موضوعية: | Cancer Research, Cancer, medicine.disease, Carboplatin, 3. Good health, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Oncology, chemistry, Downregulation and upregulation, Paclitaxel, Apoptosis, Cell culture, 030220 oncology & carcinogenesis, Lipid droplet, Cancer research, medicine, Glycolysis |
الوصف: | 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. |
تدمد: | 0020-7136 |
الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::95e4b9177530409e64fe6e4dbb873ad3Test https://doi.org/10.1002/ijc.31868Test |
حقوق: | OPEN |
رقم الانضمام: | edsair.doi...........95e4b9177530409e64fe6e4dbb873ad3 |
قاعدة البيانات: | OpenAIRE |
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