4.7 Article

Inhibition of PKM2 Enhances Sensitivity of Olaparib to Ovarian Cancer Cells and Induces DNA Damage

Journal

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
Volume 18, Issue 4, Pages 1555-1568

Publisher

IVYSPRING INT PUBL
DOI: 10.7150/ijbs.62947

Keywords

ovarian cancer; olaparib; PKM2; DNA damage; homologous recombination

Funding

  1. National Natural Science Foundation of China [81874212, 82172653]
  2. Hunan Natural Science Foundation [2021JJ 40369]
  3. Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University) Open Foundation [P201905]
  4. Huxiang Excellent Discovery Team of Hunan Province [2018RS3072]
  5. Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defect in Hunan Province [2019SK1012]
  6. Key Grant of Research and Development in Hunan Province [2020DK2002]

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This study identified that downregulation of PKM2 is a novel therapeutic strategy to enhance the effectiveness of Ola in treating ovarian cancer. Silencing PKM2 or using small molecular inhibitor Shikonin can enhance the therapeutic effect of Ola on ovarian cancer cells and reduce cell growth, migration, and induce apoptosis.
Poly (ADP-ribose) polymerase inhibitors (PARPi) have showed clinical benefit as maintenance therapy in advanced ovarian cancer by impairing the homologous recombination (HR) pathway. Pyruvate kinase M2 (PKM2), the significant cancer metabolic biomarker, integrates with DNA damage to directly promote HR. We aimed to investigate the role and molecular mechanism of PKM2 downregulation on sensitization of ovarian cancer cells to PARPi. Inhibitory effects in vitro were assessed by cell viability, clone formation, transwell assay, and flow cytometry. Downregulation of PKM2 by siRNA or small molecular inhibitor shikonin (Sk) enhanced anti-tumour activity of olaparib (Ola) in ovarian cancer cells. Silencing PKM2 or Sk synergized with Ola and reduced cell growth, colony formation and migration, and induced apoptosis. Western blot and immunofluorescence demonstrated that inhibition of PKM2 amplified Ola-induced gamma H2AX and phospho-ATM (p-ATM) activation and interfered with BRCA1 accumulation in the nucleus. A xenograft animal model demonstrated in vivo antitumor combination effect of Sk and Ola. Furthermore, Western blot and immunofluorenscent analyses of tissue samples revealed that treatment of Sk increased DNA damage, reduced expression of BRCA1 and PKM2. Therefore, this study identified that PKM2 downregulation is a novel therapeutic strategy to enhance Ola effectiveness in treating ovarian cancer.

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