Abstract
Prostate cancer is the second most common cause of cancer-related deaths worldwide. The mucin 1 (MUC1) oncoprotein is highly expressed in human prostate cancers with aggressive features. However, the role for MUC1 in occurrence and progression of castration-resistant prostate cancer (CRPC) remained elusive. In this study, we showed that solamargine, a major steroidal alkaloid glycoside, inhibited the growth of CRPC cells, which was enhanced in the presence of metformin. Furthermore, we found that solamargine increased phosphorylation of AMPKα, whereas reducing the protein expression and promoter activity of MUC1. A greater effect was observed in the presence of metformin. In addition, solamargine reduced NF-κB subunit p65 protein expression. Exogenously expressed p65 resisted solamargine-reduced MUC1 protein and promoter activity. Interestingly, exogenously expressed MUC1 attenuated solamargine-stimulated phosphorylation of AMPKα and, more importantly reversed solamargine-inhibited cell growth. Finally, solamargine increased phosphorylation of AMPKα, while inhibiting MUC1, p65 and tumor growth were observed in vivo. Overall, our results show that solamargine inhibits the growth of CRPC cells through AMPKα-mediated inhibition of p65, followed by reduction of MUC1 expression in vitro and in vivo. More importantly, metformin facilitates the antitumor effect of solamargine on CRPC cells.
Highlights
Migration and invasion of hepatocellular carcinoma cells through reduction of matrix metalloproteinase (MMP) expression[13]
We provided the evidence demonstrating that solamargine inhibited the growth of castration-resistant prostate cancer (CRPC) cells through AMPKα-mediated inhibition of p65, followed by reduction of mucin 1 (MUC1) expression in vitro and in vivo
We showed that solamargine inhibited the growth of two CRPC cell lines (PC3 and DU145) in the dose-dependent manner with significant effect observed at 6 to 8 μMfor up to 72 h (Fig. 1A)
Summary
Migration and invasion of hepatocellular carcinoma cells through reduction of matrix metalloproteinase (MMP) expression[13]. The mechanisms and potential nontoxic benefits by which this agent affects prostate cancer survival remain unknown. We need to consider the effects of tissue/tumor types, and the effectors of short/long-term AMPK signaling when investigating its role in associating with cancer. Cell surface-associated mucin 1 (MUC1), a glycosylated transmembrane protein, is highly expressed in various malignant tumors and is associated with cellular growth, invasion, metastasis[23,24]. We recently showed that curcumin inhibited growth of CRPC cells through multiple kinase-mediated inhibition of MUC1 protein[27]. The expression and functional significance of MUC1 gene in occurrence and progression of CRPC still remains poorly understood. We provided the evidence demonstrating that solamargine inhibited the growth of CRPC cells through AMPKα-mediated inhibition of p65, followed by reduction of MUC1 expression in vitro and in vivo. Metformin enhanced the antitumor effects of solamargine on CRPC cells
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