Palmatine inhibits growth and invasion in prostate cancer cell: Potential role for rpS6/NFκB/FLIP.

Abstract

Novel agents are desperately needed for improving the quality of life and 5-year survival to more than 30% for metastatic castrate-resistant prostate cancer. Previously we showed that Nexrutine, Phellodendron amurense bark extract, inhibits prostate tumor growth in vitro and in vivo. Subsequently using biochemical fractionation we identified butanol fraction contributes to the observed biological activities. We report here that palmatine, which is present in the butanol fraction, selectively inhibits growth of prostate cancer cells without significant effect on non-tumorigenic prostate epithelial cells. By screening receptor tyrosine kinases in a protein kinase array, we identified ribosomal protein S6, a downstream target of p70S6K and the Akt/mTOR signaling cascade as a potential target. We further show that palmatine treatment is associated with decreased activation of NFκB and its downstream target gene FLIP. These events led to inhibition of invasion. Similar results were obtained using parent extract Nexrutine (Nx) suggesting that palmatine either in the purified form or as one of the components in Nx is a potent cytotoxic agent with tumor invasion inhibitory properties. Synergistic inhibition of rpS6/NFκB/FLIP axis with palmatine may have therapeutic potential for the treatment of prostate cancer and possibly other malignancies with their constitutive activation. These data support a biological link between rpS6/NFκB/FLIP in mediating palmatine-induced inhibitory effects and warrants additional preclinical studies to test its therapeutic efficacy.

• Authors: Heather G Hambright, Izhar Singh Batth, Jianping Xie, Rita Ghosh, Addanki Pratap Kumar
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 54 Issue 10 Pg. 1227-34 (Oct 2015) ISSN: 1098-2744 [Electronic] United States
• PMID: 25043857 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Berberine Alkaloids
• CASP8 and FADD-Like Apoptosis Regulating Protein
• NF-kappa B
• Nexrutine
• Plant Extracts
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• palmatine

Topics

• Berberine Alkaloids (pharmacology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Epithelial Cells (drug effects, metabolism)
• Humans
• Male
• NF-kappa B (metabolism)
• Neoplasm Invasiveness (prevention & control)
• Plant Extracts (pharmacology)
• Prostate (drug effects, metabolism)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Ribosomal Protein S6 Kinases (metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)