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

Ling Yin, Yongji Zeng, Renya Zeng, Yuanhong Chen, Tian Li Wang, Kerry J. Rodabaugh, Fang Yu, Amarnath Natarajan, Adam R. Karpf, Jixin Dong

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)6772-6785
Number of pages14
JournalOncogene
Volume40
Issue number50
DOIs
StatePublished - Dec 16 2021
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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