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Developing Folate-Conjugated miR-34a Therapeutic for Prostate Cancer: Challenges and Promises.
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- المؤلفون: Li, Wen1,2 (AUTHOR) ; Wang, Yunfei1 (AUTHOR) ; Liu, Xiaozhuo1 (AUTHOR) ; Wu, Shan1 (AUTHOR) ; Wang, Moyi1 (AUTHOR); Turowski, Steven G.3 (AUTHOR); Spernyak, Joseph A.3 (AUTHOR); Tracz, Amanda1 (AUTHOR); Abdelaal, Ahmed M.4 (AUTHOR); Sudarshan, Kasireddy4 (AUTHOR); Puzanov, Igor5 (AUTHOR); Chatta, Gurkamal5 (AUTHOR); Kasinski, Andrea L.4 (AUTHOR); Tang, Dean G.1,2 (AUTHOR)
- المصدر:
International Journal of Molecular Sciences. Feb2024, Vol. 25 Issue 4, p2123. 19p.
- الموضوع:
- معلومة اضافية
- نبذة مختصرة :
Prostate cancer (PCa) remains a common cancer with high mortality in men due to its heterogeneity and the emergence of drug resistance. A critical factor contributing to its lethality is the presence of prostate cancer stem cells (PCSCs), which can self-renew, long-term propagate tumors, and mediate treatment resistance. MicroRNA-34a (miR-34a) has shown promise as an anti-PCSC therapeutic by targeting critical molecules involved in cancer stem cell (CSC) survival and functions. Despite extensive efforts, the development of miR-34a therapeutics still faces challenges, including non-specific delivery and delivery-associated toxicity. One emerging delivery approach is ligand-mediated conjugation, aiming to achieve specific delivery of miR-34a to cancer cells, thereby enhancing efficacy while minimizing toxicity. Folate-conjugated miR-34a (folate–miR-34a) has demonstrated promising anti-tumor efficacy in breast and lung cancers by targeting folate receptor α (FOLR1). Here, we first show that miR-34a, a TP53 transcriptional target, is reduced in PCa that harbors TP53 loss or mutations and that miR-34a mimic, when transfected into PCa cells, downregulated multiple miR-34a targets and inhibited cell growth. When exploring the therapeutic potential of folate–miR-34a, we found that folate–miR-34a exhibited impressive inhibitory effects on breast, ovarian, and cervical cancer cells but showed minimal effects on and targeted delivery to PCa cells due to a lack of appreciable expression of FOLR1 in PCa cells. Folate–miR-34a also did not display any apparent effect on PCa cells expressing prostate-specific membrane antigen (PMSA) despite the reported folate's binding capability to PSMA. These results highlight challenges in the specific delivery of folate–miR-34a to PCa due to a lack of target (receptor) expression. Our study offers novel insights into the challenges and promises within the field and casts light on the development of ligand-conjugated miR-34a therapeutics for PCa. [ABSTRACT FROM AUTHOR]
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