Combination of curcumin and bicalutamide enhanced the growth inhibition of androgen-independent prostate cancer cells through SAPK/JNK and MEK/ERK1/2-mediated targeting NF-κB/p65 and MUC1-C

Abstract

BackgroundProstate cancer is one of the most common malignancies in men. The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features, resulting in a poor outcome. However, the functional role for MUC1 C-terminal domain (MUC1-C) in androgen-independent prostate cancer occurrence and development has remained unclear.MethodsCell viability was measured by MTT assays. Western blot analysis was performed to measure the phosphorylation and protein expression of SAPK/JNK and ERK1/2, and MUC1-C, NF-κB subunit p65 and p50. Exogenous expression of MUC1-C, NF-κB subunit p65 was carried out by transient and electroporated transfection assays.ResultsWe showed that curcumin inhibited the growth of androgen-independent prostate cancer cells and a synergy was observed in the presence of curcumin and bicalutamide, the androgen receptor antagonist. To further explore the potential mechanism underlining this, we found that curcumin increased the phosphorylation of ERK1/2 and SAPK/JNK, which was enhanced by bicalutamide. In addition, curcumin reduced the protein expression of MUC1-C and NF-κB subunit p65, which were abrogated in the presence of the inhibitors of MEK/ERK1/2 (PD98059) and SAPK/JNK (SP60015). A further reduction was observed in the combination of curcumin with bicalutamide. Moreover, while exogenous expression of MUC1-C had little effect on curcumin-reduced p65, the overexpression of p65 reversed the effect of curcumin on MUC1-C protein expression suggesting that p65 is upstream of MUC1-C. Intriguingly, we showed that exogenous expression of MUC1-C feedback diminished the effect of curcumin on phosphorylation of ERK1/2 and SAPK/JNK, and antagonized the effect of curcumin on cell growth.ConclusionOur results show that curcumin inhibits the growth of androgen-independent prostate cancer cells through ERK1/2- and SAPK/JNK-mediated inhibition of p65, followed by reducing expression of MUC1-C protein. More importantly, there are synergistic effects of curcumin and bicalutamide. The negative feedback regulatory loop of MUC1-C to ERK1/2 and SAPK/JNK further demonstrates the role of MUC1-C that contributes to the overall responses of curcumin. This study unveils the potential molecular mechanism by which combination of curcumin with bicalutamide enhances the growth inhibition of androgen-independent prostate cancer cells.

Activation of AMPKα mediates additive effects of solamargine and metformin on suppressing MUC1 expression in castration-resistant prostate cancer cells

“…Studies have highlighted the increased expression of MUC1 and its role in tumorigenesis in various cancer types including prostate cancer274546. Our results illustrated both transcriptional and translational regulations of MUC1 by solamargine, and demonstrated a critical role of MUC1 expression in mediating the effect of solamargine on inhibition of growth of CRPC cell.…”

“…MUC1 has been shown to bind to transcriptional factor, such as nuclear factor NF-kappaB (NF-κB)/p65, and promote downstream target gene expression23. We recently showed that curcumin inhibited growth of CRPC cells through multiple kinase-mediated inhibition of MUC1 protein27. However, the expression and functional significance of MUC1 gene in occurrence and progression of CRPC still remains poorly understood.…”

Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

“…As an oncogenic factor, overexpressed MUC1 was observed in several epithelial cancers, including prostate cancer [32,49]. The regulation and interaction between p65 and MUC1 were also demonstrated in other studies [34,50,51]. By binding to the promoter regions, the MUC1/NF-κB complex could promote certain gene expression in different cancer cells [34,52].…”

Peroxiredoxin 1 – an antioxidant enzyme in cancer

“…PRDX1 overexpression is also found in human prostate cancer specimens and prostate cancer cell lines [17,100]. Prostate cancer risk and prognosis are adversely associated with a number of inflammatory and angiogenic mediators, including Toll-like receptor 4 (TLR4), NF-jB and VEGF [101][102][103][104]. Elevated PRDX1 increases prostate tumour vasculature, and shows up-regulation of angiogenic proteins such as VEGF in the tumour region.…”