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

Szczegóły
Abstrakt

Tytuł:: Protein kinase RNA-activated controls mitotic progression and determines paclitaxel chemosensitivity through B-cell lymphoma 2 in ovarian cancer.
Autorzy:: Yin L; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
Zeng Y; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Zeng R; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Chen Y; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Wang TL; Department of Pathology and Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, 21205, USA.
Rodabaugh KJ; Department of Gynecologic Oncology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Yu F; Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Natarajan A; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Karpf AR; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Dong J; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA. .
Źródło:: Oncogene [Oncogene] 2021 Dec; Vol. 40 (50), pp. 6772-6785. Date of Electronic Publication: 2021 Nov 19.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural
Język:: English
Imprint Name(s):: Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-
MeSH Terms:: Mitosis*
Biomarkers, Tumor/*metabolism
Gene Expression Regulation, Neoplastic/*drug effects
Ovarian Neoplasms/*drug therapy
Paclitaxel/*pharmacology
Proto-Oncogene Proteins c-bcl-2/*metabolism
eIF-2 Kinase/*metabolism
Animals ; Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis ; Biomarkers, Tumor/genetics ; Cell Movement ; Cell Proliferation ; Female ; Humans ; Mice ; Mice, Nude ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Proto-Oncogene Proteins c-bcl-2/genetics ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; eIF-2 Kinase/genetics
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Grant Information:: P30 CA036727 United States CA NCI NIH HHS; P30 GM106397 United States GM NIGMS NIH HHS; R01 CA273226 United States CA NCI NIH HHS; R01 GM109066 United States GM NIGMS NIH HHS
Substance Nomenclature:: 0 (Antineoplastic Agents, Phytogenic)
0 (BCL2 protein, human)
0 (Biomarkers, Tumor)
0 (Proto-Oncogene Proteins c-bcl-2)
EC 2.7.11.1 (EIF2AK2 protein, human)
EC 2.7.11.1 (eIF-2 Kinase)
P88XT4IS4D (Paclitaxel)
Entry Date(s):: Date Created: 20211120 Date Completed: 20220103 Latest Revision: 20240214
Update Code:: 20240214
PubMed Central ID:: PMC8688329
DOI:: 10.1038/s41388-021-02117-5
PMID:: 34799660
: Czasopismo naukowe

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.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

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