MiR-15b-3p weakens bicalutamide sensitivity in prostate cancer via targeting KLF2 to suppress ferroptosis

Zhang, Chunlin; Yu, Haitao; Bai, Xuesong; Zhou, Xiang; Feng, Zhenwei; Li, Yang; Peng, Xiang; Mei, Yuhua; Li, Li; Gou, Xin; Deng, Yuanzhong; Chen, Guo

doi:10.7150/jca.92379

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J Cancer 2024; 15(8):2306-2317. doi:10.7150/jca.92379 This issue Cite

Research Paper

MiR-15b-3p weakens bicalutamide sensitivity in prostate cancer via targeting KLF2 to suppress ferroptosis

Chunlin Zhang^1,2, Haitao Yu^1,2, Xuesong Bai^1,2, Xiang Zhou^1,2, Zhenwei Feng^1,2, Yang Li^1,2, Xiang Peng^1,2, Yuhua Mei^1,2, Li Li^1,2, Xin Gou¹, Yuanzhong Deng^1✉, Guo Chen^1,2✉

1. Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
2. Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China.

Citation:

Zhang C, Yu H, Bai X, Zhou X, Feng Z, Li Y, Peng X, Mei Y, Li L, Gou X, Deng Y, Chen G. MiR-15b-3p weakens bicalutamide sensitivity in prostate cancer via targeting KLF2 to suppress ferroptosis. J Cancer 2024; 15(8):2306-2317. doi:10.7150/jca.92379. https://www.jcancer.org/v15p2306.htm

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Abstract

Bicalutamide (BIC) resistance impedes the treatment of prostate cancer (PCa) and seems to involve ferroptosis; however, the underlying mechanism remains unclear. Our study aimed to explore how miR-15b-3p modulates ferroptosis in response to BIC resistance and determine whether the miRNA is suitable for early screening of PCa. Here, we found that PCa tissues had significantly higher miR-15b-3p expression than adjacent normal tissues. Analysis of blood samples in patients who underwent prostate-specific antigen (PSA) screening revealed that miR-15b-3p was a more accurate diagnostic than PSA (miR-15b-3p area under the curve [AUC] = 0.941, PSA AUC = 0.815). In vitro experiments then demonstrated that miR-15b-3p expression was markedly higher in LNCaP, PC-3, and DU145 cells than in RWPE-1 cells. Treatment with BIC decreased miR-15b-3p expression and progressive ferroptosis. Mechanistically, we identified KLF2 as the downstream target of miR-15b-3p. Overexpressing KLF2 facilitated ferroptosis via augmenting MDA and iron concentrations, in turn inhibiting the SLC7A11/GPX4 axis and decreasing GSH concentration. Through modulating ferroptosis, miR-15b-3p mimic and inhibitor weakened and enhanced BIC sensitivity, respectively. Furthermore, BIC treatment limited xenograft tumor volume in vivo, whereas agomir-15b-3p promoted tumor growth, indicating that miR-15b-3p attenuated the tumor-suppressive effects of BIC. Taken together, our results suggested that miR-15b-3p is crucial to BIC resistance, specifically via targeting KLF2 and thereby suppressing ferroptosis. High miR-15b-3p expression in early PCa screening should reflect a higher probability of cancer. In conclusion, miR-15b-3p has strong potential as a screening and diagnostic biomarker with reliable prospects for clinical application. Furthermore, because patients with high miR-15b-3p and low KLF2 expression have a greater risk of BIC resistance and malignant progression, targeting the miRNA and its downstream protein may be a new treatment strategy.

Keywords: miRNA, Prostate cancer, Ferroptosis, Prostate-specific antigen, Bicalutamide resistance

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APA

Zhang, C., Yu, H., Bai, X., Zhou, X., Feng, Z., Li, Y., Peng, X., Mei, Y., Li, L., Gou, X., Deng, Y., Chen, G. (2024). MiR-15b-3p weakens bicalutamide sensitivity in prostate cancer via targeting KLF2 to suppress ferroptosis. Journal of Cancer, 15(8), 2306-2317. https://doi.org/10.7150/jca.92379.

ACS

Zhang, C.; Yu, H.; Bai, X.; Zhou, X.; Feng, Z.; Li, Y.; Peng, X.; Mei, Y.; Li, L.; Gou, X.; Deng, Y.; Chen, G. MiR-15b-3p weakens bicalutamide sensitivity in prostate cancer via targeting KLF2 to suppress ferroptosis. J. Cancer 2024, 15 (8), 2306-2317. DOI: 10.7150/jca.92379.

NLM

CSE

Zhang C, Yu H, Bai X, Zhou X, Feng Z, Li Y, Peng X, Mei Y, Li L, Gou X, Deng Y, Chen G. 2024. MiR-15b-3p weakens bicalutamide sensitivity in prostate cancer via targeting KLF2 to suppress ferroptosis. J Cancer. 15(8):2306-2317.

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