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

Zhou, Sichun; Li, Duo; Xiao, Di; Wu, Tianyu; Hu, Xin; Zhang, Yu; Deng, Jun; Long, Jing; Xu, Simeng; Wu, Jingtao; Li, Gaofeng; Peng, Mei; Yang, Xiaoping

doi:10.7150/ijbs.62947

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International Journal of Medical Sciences

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Journal of Cancer

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Int J Biol Sci 2022; 18(4):1555-1568. doi:10.7150/ijbs.62947 This issue Cite

Research Paper

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

Sichun Zhou^1#, Duo Li^1#, Di Xiao¹, Tianyu Wu², Xin Hu¹, Yu Zhang², Jun Deng¹, Jing Long², Simeng Xu¹, Jingtao Wu¹, Gaofeng Li², Mei Peng², Xiaoping Yang^1✉

1. Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, 410013, China; Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Yantai University, Yantai, 264005, China
2. Department of Oncology, The Affiliated Zhuzhou Hospital of Xiangya School of Medicine, Central South University, Zhuzhou, 412007, China; Obstetrics and Gynecology Department, Xiangya Hospital, Central South University, Changsha, 410008, China; Departments of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, China
# These authors contributed equally to this work.

Citation:

Zhou S, Li D, Xiao D, Wu T, Hu X, Zhang Y, Deng J, Long J, Xu S, Wu J, Li G, Peng M, Yang X. Inhibition of PKM2 Enhances Sensitivity of Olaparib to Ovarian Cancer Cells and Induces DNA Damage. Int J Biol Sci 2022; 18(4):1555-1568. doi:10.7150/ijbs.62947. https://www.ijbs.com/v18p1555.htm

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Abstract

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 γH2AX 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.

Keywords: ovarian cancer, olaparib, PKM2, DNA damage, homologous recombination

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APA

Zhou, S., Li, D., Xiao, D., Wu, T., Hu, X., Zhang, Y., Deng, J., Long, J., Xu, S., Wu, J., Li, G., Peng, M., Yang, X. (2022). Inhibition of PKM2 Enhances Sensitivity of Olaparib to Ovarian Cancer Cells and Induces DNA Damage. International Journal of Biological Sciences, 18(4), 1555-1568. https://doi.org/10.7150/ijbs.62947.

ACS

Zhou, S.; Li, D.; Xiao, D.; Wu, T.; Hu, X.; Zhang, Y.; Deng, J.; Long, J.; Xu, S.; Wu, J.; Li, G.; Peng, M.; Yang, X. Inhibition of PKM2 Enhances Sensitivity of Olaparib to Ovarian Cancer Cells and Induces DNA Damage. Int. J. Biol. Sci. 2022, 18 (4), 1555-1568. DOI: 10.7150/ijbs.62947.

NLM

CSE

Zhou S, Li D, Xiao D, Wu T, Hu X, Zhang Y, Deng J, Long J, Xu S, Wu J, Li G, Peng M, Yang X. 2022. Inhibition of PKM2 Enhances Sensitivity of Olaparib to Ovarian Cancer Cells and Induces DNA Damage. Int J Biol Sci. 18(4):1555-1568.

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