title: Curcumin attenuates β-catenin signaling in prostate cancer cells through activation of protein kinase D1.
abstract: Prostate cancer is the most commonly diagnosed cancer affecting 1 in 6 males in the US. Understanding the molecular basis of prostate cancer progression can serve as a tool for early diagnosis and development of novel treatment strategies for this disease. Protein Kinase D1 (PKD1) is a multifunctional kinase that is highly expressed in normal prostate. The decreased expression of PKD1 has been associated with the progression of prostate cancer. Therefore, synthetic or natural products that regulate this signaling pathway can serve as novel therapeutic modalities for prostate cancer prevention and treatment. Curcumin, the active ingredient of turmeric, has shown anti-cancer properties via modulation of a number of different molecular pathways. Herein, we have demonstrated that curcumin activates PKD1, resulting in changes in β-catenin signaling by inhibiting nuclear β-catenin transcription activity and enhancing the levels of membrane β-catenin in prostate cancer cells. Modulation of these cellular events by curcumin correlated with decreased cell proliferation, colony formation and cell motility and enhanced cell-cell aggregation in prostate cancer cells. In addition, we have also revealed that inhibition of cell motility by curcumin is mediated by decreasing the levels of active cofilin, a downstream target of PKD1. The potent anti-cancer effects of curcumin in vitro were also reflected in a prostate cancer xenograft mouse model. The in vivo inhibition of tumor growth also correlated with enhanced membrane localization of β-catenin. Overall, our findings herein have revealed a novel molecular mechanism of curcumin action via the activation of PKD1 in prostate cancer cells.
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, South Dakota, United States of America.
authors.forename: Vasudha
authors.initials: V
authors.lastname: Sundram
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Chauhan
authors.forename: Mara
authors.initials: M
authors.lastname: Ebeling
authors.forename: Meena
authors.initials: M
authors.lastname: Jaggi
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D051338:Cofilin 1 / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000037:antagonists & inhibitors*
chemical_list: D051338:Cofilin 1; D034741:RNA, Small Interfering; D051176:beta Catenin; C089212:protein kinase D; D011493:Protein Kinase C; D003474:Curcumin