Curcumin Upregulates miR-148a to Increase the Chemosensitivity of CD44-Positive Prostate Cancer Stem Cells to Paclitaxel Through Targeting the MSK1/IRS1 axis

Abstract

Background In men, prostate cancer (PC) is the second most common cause of cancer-related death. However, paclitaxel resistance is a major challenge in advanced PC. Curcumin, a natural antioxidant, has been demonstrated to have cytotoxic effects on cancer stem cells (CSCs). The goal of this study is to explore if curcumin can help lower chemoresistance to paclitaxel through the regulation of miR-148a-mediated apoptosis in prostate CSCs.

Methods The 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and 4′,6-diamidino-2-phenylindole (DAPi) labeling were used to determine cell survival. Immunohistochemistry was used to detect the expression of P-glycoprotein protein (P-gp) and CD44 proteins. Finally, real-time PCR was used to evaluate the regulatory effects of curcumin and paclitaxel on miR-148a and its target genes.

Results Curcumin and paclitaxel co-treatment significantly reduced the IC₅₀ value in CD44⁺cells compared to paclitaxel alone. Additionally, combining these drugs considerably increased apoptosis in CD44⁺cells. We also discovered that when curcumin and paclitaxel were combined, the expression of CD44 and P-gp was significantly reduced compared to paclitaxel alone. Curcumin and paclitaxel co-treatment also increased miR-148a levels and regulated the levels of its target genes MSK1 and IRS1.

Conclusion Curcumin may restore paclitaxel sensitivity by raising miR-148a expression and inhibiting its target genes.

Keywords

prostate cancer - cancer stem cells - curcumin - paclitaxel - miR-148a - P-gp - CD44

Publication History

Received: 08 April 2022

Accepted: 30 May 2022

Article published online:
22 July 2022

• References

• 1 Richardson GD, Robson CN, Lang SH. et al. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 2004; 117: 3539-3545 DOI: 10.1242/jcs.01222.
• 2 Li H, Tang DG. Prostate cancer stem cells and their potential roles in metastasis. Journal of surgical oncology 2011; 103: 558-562 DOI: 10.1002/jso.21806.
• 3 Chen C, Zhao S, Karnad A. et al. The biology and role of CD44 in cancer progression: therapeutic implications. Journal of hematology & oncology 2018; 11: 64 DOI: 10.1186/s13045-018-0605-5.
• 4 Aggarwal BB. Prostate cancer and curcumin: add spice to your life. Cancer biology & therapy 2008; 7: 1436-1440 DOI: 10.4161/cbt.7.9.6659.
• 5 Kopczyńska E. Role of microRNAs in the resistance of prostate cancer to docetaxel and paclitaxel. Contemp Oncol 2015; 19: 423 DOI: 10.5114/wo.2015.56648.
• 6 Liu Y, Sun H, Makabel B. et al. The targeting of non‑coding RNAs by curcumin: Facts and hopes for cancer therapy (Review). Oncology reports 2019; 42: 20-34 DOI: 10.3892/or.2019.7148.
• 7 Mokabber H, Vatankhah MA, Najafzadeh N. The regulatory role of microRNAs in the development, cyclic changes, and cell differentiation of the hair follicle. Process Biochemistry 2022; 114: 36-41 DOI: 10.1016/j.procbio.2022.01.016.
• 8 Nejati K, Alivand M, Arabzadeh A. MicroRNA-22 in female malignancies: Focusing on breast, cervical, and ovarian cancers. Pathology, research and practice 2021; 223: 153452 DOI: 10.1016/j.prp.2021.153452.
• 9 Momtazi AA, Shahabipour F, Khatibi S. et al. Curcumin as a MicroRNA Regulator in Cancer: A Review. Reviews of physiology, biochemistry and pharmacology 2016; 171: 1-38 DOI: 10.1007/112_2016_3.
• 10 Pahlavan Y, Mohammadi Nasr M, Dalir Abdolahinia E. et al. Prominent roles of microRNA-142 in cancer. Pathology, research and practice 2020; 216: 153220 DOI: 10.1016/j.prp.2020.153220.
• 11 Lombard AP, Mooso BA, Libertini SJ. et al. miR-148a dependent apoptosis of bladder cancer cells is mediated in part by the epigenetic modifier DNMT1. Mol Carcinog 2016; 55: 757-767 DOI: 10.1002/mc.22319.
• 12 Zhou X, Zhao F, Wang ZN. et al. Altered expression of miR-152 and miR-148a in ovarian cancer is related to cell proliferation. Oncology reports 2012; 27: 447-454 DOI: 10.3892/or.2011.1482.
• 13 Sarkhani E, Najafzadeh N, Tata N. et al. Molecular mechanisms of methylsulfonylmethane and allicin in the inhibition of CD44± breast cancer cells growth. Journal of Functional Foods 2017; 39: 50-57 DOI: 10.1016/j.jff.2017.10.007.
• 14 Dorai T, Dutcher JP, Dempster DW. et al. Therapeutic potential of curcumin in prostate cancer-V: Interference with the osteomimetic properties of hormone refractory C4-2B prostate cancer cells. The Prostate 2004; 60: 1-17 DOI: 10.1002/pros.10359.
• 15 Zhang H, Yu T, Wen L. et al. Curcumin enhances the effectiveness of cisplatin by suppressing CD133+cancer stem cells in laryngeal carcinoma treatment. Experimental and therapeutic medicine 2013; 6: 1317-1321
• 16 Yu Y, Kanwar SS, Patel BB. et al. Elimination of colon cancer stem-like cells by the combination of curcumin and FOLFOX. Translational oncology 2009; 2: 321-328
• 17 Aditya NP, Shim M, Yang H. et al. Antiangiogenic effect of combined treatment with curcumin and genistein on human prostate cancer cell line. Journal of Functional Foods 2014; 8: 204-213 DOI: 10.1016/j.jff.2014.03.014.
• 18 Boevé LMS, Hulshof MCCM, Vis AN. et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol 2019; 75: 410-418 DOI: 10.1016/j.eururo.2018.09.008.
• 19 Gann PH. Risk factors for prostate cancer. Reviews in urology 2002; 4 Suppl 5 S3-S10
• 20 Pienta KJ, Smith DC. Advances in prostate cancer chemotherapy: a new era begins. CA: a cancer journal for clinicians 2005; 55: 300-318 quiz 323-305 DOI: 10.3322/canjclin.55.5.300.
• 21 Nawara H, Afify SM, Hassan G. et al. Paclitaxel-Based Chemotherapy Targeting Cancer Stem Cells from Mono- to Combination Therapy. Biomedicines 2021; 9: 1-17 DOI: 10.3390/biomedicines9050500.
• 22 Liu T, Chi H, Chen J. et al. Curcumin suppresses proliferation and in vitro invasion of human prostate cancer stem cells by ceRNA effect of miR-145 and lncRNA-ROR. Gene 2017; 631: 29-38 DOI: 10.1016/j.gene.2017.08.008.
• 23 Banerjee S, Rajamani P, Ramawat K. Cellular, molecular, and biological perspective of polyphenols in chemoprevention and therapeutic adjunct in cancer. Natural Products Springer-Verlag; Berlin, Heidelberg: 2013: 2175-2253 DOI: 10.1007/978-3-642-22144-6_72
• 24 Toden S, Okugawa Y, Jascur T. et al. Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis 2015; 36: 355-367 DOI: 10.1093/carcin/bgv006.
• 25 Zhou X, Wang W, Li P. et al. Curcumin Enhances the Effects of 5-Fluorouracil and Oxaliplatin in Inducing Gastric Cancer Cell Apoptosis Both In Vitro and In Vivo. Oncology research 2016; 23: 29-34 DOI: 10.3727/096504015x14452563486011.
• 26 Wei Y, Pu X, Zhao L. Preclinical studies for the combination of paclitaxel and curcumin in cancer therapy (Review). Oncology reports 2017; 37: 3159-3166 DOI: 10.3892/or.2017.5593.
• 27 Fujita Y, Kojima K, Ohhashi R. et al. MiR-148a attenuates paclitaxel resistance of hormone-refractory, drug-resistant prostate cancer PC3 cells by regulating MSK1 expression. Journal of biological chemistry 2010; 285: 19076-19084 DOI: 10.1074/jbc.M109.079525.
• 28 Giovannucci E, Liu Y, Platz EA. et al. Risk factors for prostate cancer incidence and progression in the health professionals follow-up study. International journal of cancer 2007; 121: 1571-1578 DOI: 10.1002/ijc.22788.
• 29 Wu H, Liu Q, Cai T. et al. Induction of microRNA-146a is involved in curcumin-mediated enhancement of temozolomide cytotoxicity against human glioblastoma. Mol Med Rep 2015; 12: 5461-5466 DOI: 10.3892/mmr.2015.4087.
• 30 Liu J, Li M, Wang Y. et al. Curcumin sensitizes prostate cancer cells to radiation partly via epigenetic activation of miR-143 and miR-143 mediated autophagy inhibition. Journal of drug targeting 2017; 25: 645-652 DOI: 10.1080/1061186x.2017.1315686.
• 31 Miletti-González KE, Chen S, Muthukumaran N. et al. The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer. Cancer research 2005; 65: 6660-6667 DOI: 10.1158/0008-5472.can-04-3478.
• 32 Li Y, Zhang T. Targeting cancer stem cells by curcumin and clinical applications. Cancer letters 2014; 346: 197-205 DOI: 10.1016/j.canlet.2014.01.012.
• 33 Liu C, Kelnar K, Liu B. et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nature medicine 2011; 17: 211-215 DOI: 10.1038/nm.2284.
• 34 Saini S, Majid S, Shahryari V. et al. miRNA-708 control of CD44(+) prostate cancer-initiating cells. Cancer research 2012; 72: 3618-3630 DOI: 10.1158/0008-5472.can-12-0540.
• 35 Punfa W, Suzuki S, Pitchakarn P. et al. Curcumin-loaded PLGA nanoparticles conjugated with anti- P-glycoprotein antibody to overcome multidrug resistance. Asian Pacific journal of cancer prevention : APJCP 2014; 15: 9249-9258 DOI: 10.7314/apjcp.2014.15.21.9249.
• 36 Mathur A, Abd Elmageed ZY, Liu X. et al. Subverting ER-stress towards apoptosis by nelfinavir and curcumin coexposure augments docetaxel efficacy in castration resistant prostate cancer cells. PloS one 2014; 9: e103109 DOI: 10.1371/journal.pone.0103109.
• 37 Tang XQ, Bi H, Feng JQ. et al. Effect of curcumin on multidrug resistance in resistant human gastric carcinoma cell line SGC7901/VCR. Acta pharmacologica Sinica 2005; 26: 1009-1016 DOI: 10.1111/j.1745-7254.2005.00149.x.
• 38 Buhrmann C, Yazdi M, Dezfouli AB. et al. Significant decrease in the viability and tumor stem cell marker expression in tumor cell lines treated with curcumin. J Herb Med 2020; 22: 100339 DOI: 10.1016/j.hermed.2020.100339.