Androgen-ablative therapies inducing CXCL8 regulates mTORC1/SREBP2-dependent cholesterol biosynthesis to support progression of androgen receptor negative prostate cancer cells.

Autor: Xiong X; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, SC, China., Zhang S; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, SC, China., Zhu W; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, SC, China., Du J; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, SC, China., Liao X; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, SC, China., Hu S; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, SC, China., Yang J; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, SC, China., Zheng W; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, SC, China., Qiu S; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, SC, China.; Center of Biomedical Big Data, West China Hospital Sichuan University, Chengdu, SC, China., Xu H; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, SC, China. hangxu@wchscu.cn., Wei Q; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, SC, China. weiqiang933@126.com., Yang L; Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, SC, China. wycleflue@163.com.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2024 Nov; Vol. 43 (47), pp. 3456-3468. Date of Electronic Publication: 2024 Oct 05.
DOI: 10.1038/s41388-024-03181-3
Abstrakt: Treatment with androgen-ablative therapies effectively inhibited androgen receptor (AR)-positive (AR+) prostate cancer (PCa) cell subtypes, but it resulted in an increase in AR-negative (AR-) PCa cell subtypes. The present study aimed to investigate the debated mechanisms responsible for the changing proportion of cell types, identifying CXCL8 as a synthetic essential effector of AR- PCa cells. AR- PCa cells were found to be susceptible to CXCL8 depletion or inhibition, which impaired their survival. Mechanistically, androgen-ablative therapies resulted in the suppression of AR signaling, leading to the upregulation of CXCL8 gene transcription. CXCL8, in turn, activated the mTORC1 pathway, which increased de novo cholesterol synthesis by activating sterol regulatory element-binding protein-2 (SREBP2). Together, these results suggested that the CXCL8-mTORC1-SREBP2 axis contributed to the exacerbation of tumorigenicity in AR- PCa cells under androgen-ablative therapies.
Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate We obtained written informed consent from the patients and permission from Institutional Research Ethics Committee to collect and use these clinical data, and were carried out in accordance with International Ethical Guidelines for Health-related Research Involving Humans. All experimental animal procedures were performed according to guidelines approved by the Institutional Animal Care and Use Committees (IACUCs) and were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals (National Academies Press, 2011).
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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