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Protein kinase RNA-activated controls mitotic progression and determines paclitaxel chemosensitivity through B-cell lymphoma 2 in ovarian cancer

Oncogene volume 40, pages 6772–6785 (2021)Cite this article

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Abstract

Anti-tubulin agents, such as paclitaxel, have been used extensively for treatment of several types of cancer, including ovarian, lung, breast, and pancreatic cancers. Despite their wide use in cancer treatment, however, patient response is highly variable and drug resistance remains a major clinical issue. Protein kinase RNA-activated (PKR) plays a critical role in immune response to viral infection. We identified PKR as a phospho-protein in response to anti-tubulin agents and this phosphorylation occurs independent of its own kinase activity. PKR is phosphorylated by cyclin-dependent kinase 1 (CDK1) during anti-tubulin treatment and unperturbed mitosis and that PKR regulates mitotic progression in a phosphorylation-dependent manner. Furthermore, inactivation of PKR confers resistance to paclitaxel in ovarian and breast cancer cells in vitro and in vivo. PKR expression levels and activity are decreased in chemotherapeutic recurrent ovarian cancer patients. Mechanistically, our findings suggest that PKR controls paclitaxel chemosensitivity through repressing Bcl2 expression. Pharmacological inhibition of Bcl2 with FDA-approved agent venetoclax overcomes paclitaxel resistance in preclinical animal models of ovarian cancer. Our results suggest that PKR is a critical determinant of paclitaxel cytotoxicity and that PKR-Bcl2 axis as a potential therapeutic target for the treatment of recurrent drug-resistant ovarian tumors.

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Fig. 1: CDK1/cyclin B1 kinase complex phosphorylates PKR during mitotic arrest.
Fig. 2: Phosphorylation of PKR is required for precise mitosis in cancer cells.
Fig. 3: PKR regulates Taxol chemosensitivity in cancer cells.
Fig. 4: PKR promotes tumorigenesis and paclitaxel sensitivity in vivo.
Fig. 5: Mitotic phosphorylation of PKR is required for cancer cell growth and paclitaxel chemosensitivity.
Fig. 6: PKR regulates paclitaxel sensitivity through Bcl2.
Fig. 7: Bcl2 inhibition reverses paclitaxel resistance in vivo.

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Acknowledgements

We are very grateful to Dr. Michael Seiden for the SKOV3/SKOV3-Taxol resistant cell lines [43]. All fluorescence images were acquired by Zeiss LSM 710 or LSM 800 confocal microscopes at the Advanced Microscopy Core at the University of Nebraska Medical Center. The core is supported in part by grant P30 GM106397 from the National Institutes of Health (NIH). Research in the Dong laboratory is supported by Fred & Pamela Buffett Cancer Center Support Grant (P30 CA036727), grants P30 GM106397 and R01 GM109066 from the NIH. We also thank Dr. Joyce Solheim for critical reading and comments on the manuscript.

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  1. Ling Yin

    Present address: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

Authors and Affiliations

  1. Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Ling Yin, Yongji Zeng, Renya Zeng, Yuanhong Chen, Amarnath Natarajan, Adam R. Karpf & Jixin Dong

  2. Department of Pathology and Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, 21205, USA

    Tian-Li Wang

  3. Department of Gynecologic Oncology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Kerry J. Rodabaugh

  4. Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Fang Yu

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Contributions

JD and LY designed and wrote the paper. LY, YZ, RZ, and YC performed the experiments, analyzed the data, and interpreted the results. YC also provided technical support. KJR, AN, and ARK contributed to data analysis and results interpretation. FY performed statistical analysis. TLW provided the TMAs. All authors reviewed and approved the manuscript prior to submission.

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Correspondence to Jixin Dong.

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Yin, L., Zeng, Y., Zeng, R. et al. Protein kinase RNA-activated controls mitotic progression and determines paclitaxel chemosensitivity through B-cell lymphoma 2 in ovarian cancer. Oncogene 40, 6772–6785 (2021). https://doi.org/10.1038/s41388-021-02117-5

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