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.

Recent Advances in Curcumin-Based Combination Nanomedicines for Cancer Therapy

“…Cur has also been shown to improve the sensitivity of prostate cancer cells to PTX through targeting mitogen and stress-activated kinase 1 (MSK1) and insulin receptor substrate-1 (IRS-1) signaling. The combination remarkably augmented apoptosis and reduced the expression of P-gp in CD44 + cells in comparison to Cur or PTX [ 50 ]. Furthermore, the combination of Cur and metformin displayed a synergistic impact in triggering apoptosis in LNCaP prostate cancer cells, as indicated by suppressing mTOR signaling, upregulating Bax and PUMA, and reducing the Bcl-2 expression [ 51 ].…”

Synergistic effects of flavonoids and paclitaxel in cancer treatment: a systematic review

“…According to previous studies combined treatment of paclitaxel with some natural compounds such as curcumin, also reduced adverse effects and increased the chemosensitivity of cancer cells to paclitaxel [ 33 , 34 ].…”