Abrogation of ATR function preferentially augments cisplatin-induced cytotoxicity in PTEN-deficient breast cancer cells.

Autor: Zhao JL; Department of Pharmacology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China., Yang J; Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China., Li K; Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China., Chen Y; Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China., Tang M; Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China., Zhu HL; Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: 13551287548@139.com., Nie CL; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China., Yuan Z; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China., Zhao XY; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: zhaoxinyu@scu.edu.cn.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2023 Nov 01; Vol. 385, pp. 110740. Date of Electronic Publication: 2023 Oct 05.
DOI: 10.1016/j.cbi.2023.110740
Abstrakt: Targeting replication stress response is currently emerging as new therapeutic strategy for cancer treatment, based on monotherapy and combination approaches. As a key sensor in response to DNA damage, ataxia telangiectasia and rad3-related (ATR) kinase has become a potential therapeutic target as tumor cells are to rely heavily on ATR for survival. The tumor suppressor phosphatase and tensin homolog (PTEN) plays a crucial role in maintaining chromosome integrity. Although ATR inhibition was recently confirmed to show a synergistic inhibitory effect in PTEN-deficient triple-negative breast cancer cells, the molecular mechanism needs to be further elucidated. Additionally, whether the PTEN-deficient breast cancer cells are more preferentially sensitized than PTEN-wild type breast cancer cells to cisplatin plus ATR inhibitor remains unanswered. We demonstrate PTEN dysfunction promotes the killing effect of ATR blockade through the use of RNA interference for PTEN and a highly selective ATR inhibitor VE-821, and certify that VE-821 (1.0 μmol/L) aggravates cytotoxicity of cisplatin on breast cancer cells, especially PTEN-null MDA-MB-468 cells which show more chemoresistance than PTEN-expressing MDA-MB-231 cells. The co-treatment with VE-821 and cisplatin significantly reduced cell viability and proliferative capacity compared with cisplatin mono-treatment (P < 0.05). The increased cytotoxic activity is tied to the enhanced poly (ADP-ribose) polymerase (PARP) cleavage and consequently cell death due to the decrease in phosphorylation levels of checkpoint kinases 1 and 2 (CHK1/2), the reduction of radiation sensitive 51 (RAD51) foci and the increase in phosphorylation of the histone variant H2AX (γ-H2AX) foci (P < 0.05) as well. Together, these findings suggest combination therapy of ATR inhibitor and cisplatin may offer a potential therapeutic strategy for breast tumors.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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