Inhibition of PFKFB3 induces cell death and synergistically enhances chemosensitivity in endometrial cancer
| العنوان: | Inhibition of PFKFB3 induces cell death and synergistically enhances chemosensitivity in endometrial cancer |
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| المؤلفون: | Yinan Xiao, Viji Shridhar, Julie Staub, Chaolin Deng, Sayantani Sarkar Bhattacharya, Upasana Ray, Ling Jin, Xiaoling Fang, Eleftheria Kalogera, Haotian Xu, Ye Guan, Prabhu Thirusangu |
| المصدر: | Oncogene |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, Programmed cell death, Phosphofructokinase-2, Pyridines, Apoptosis, Biology, Article, Carboplatin, chemistry.chemical_compound, Targeted therapies, Endometrial cancer, Downregulation and upregulation, Cell Line, Tumor, Autophagy, Genetics, medicine, Chemotherapy, Humans, Molecular Biology, Protein kinase B, Cell Proliferation, Cisplatin, Cell growth, TOR Serine-Threonine Kinases, Xenograft Model Antitumor Assays, Endometrial Neoplasms, Gene Expression Regulation, Neoplastic, chemistry, Drug Resistance, Neoplasm, Cell culture, Quinolines, Cancer research, Female, Signal Transduction, medicine.drug |
| الوصف: | The advanced or recurrent endometrial cancer (EC) has a poor prognosis because of chemoresistance. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a glycolytic enzyme, is overexpressed in a variety of human cancers and plays important roles in promoting tumor cell growth. Here, we showed that high expression of PFKFB3 in EC cell lines is associated with chemoresistance. Pharmacological inhibition of PFKFB3 with PFK158 and or genetic downregulation of PFKFB3 dramatically suppressed cell proliferation and enhanced the sensitivity of EC cells to carboplatin (CBPt) and cisplatin (Cis). Moreover, PFKFB3 inhibition resulted in reduced glucose uptake, ATP production, and lactate release. Notably, we found that PFK158 with CBPt or Cis exerted strong synergistic antitumor activity in chemoresistant EC cell lines, HEC-1B and ARK-2 cells. We also found that the combination of PFK158 and CBPt/Cis induced apoptosis- and autophagy-mediated cell death through inhibition of the Akt/mTOR signaling pathway. Mechanistically, we found that PFK158 downregulated the CBPt/Cis-induced upregulation of RAD51 expression and enhanced CBPt/Cis-induced DNA damage as demonstrated by an increase in γ-H2AX levels in HEC-1B and ARK-2 cells, potentially revealing a means to enhance PFK158-induced chemosensitivity. More importantly, PFK158 treatment, either as monotherapy or in combination with CBPt, led to a marked reduction in tumor growth in two chemoresistant EC mouse xenograft models. These data suggest that PFKFB3 inhibition alone or in combination with standard chemotherapy may be used as a novel therapeutic strategy for improved therapeutic efficacy and outcomes of advanced and recurrent EC patients. |
| تدمد: | 1476-5594 0950-9232 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9889ad4045dd12b8f7e423ae5438c349Test https://doi.org/10.1038/s41388-020-01621-4Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9889ad4045dd12b8f7e423ae5438c349 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765594 09509232 |
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