Silymarin induces cyclin D1 proteasomal degradation via its phosphorylation of threonine-286 in human colorectal cancer cells

• Published in: International immunopharmacology Vol. 24; no. 1; pp. 1 - 6
• Main Authors: Eo, Hyun Ji, Park, Gwang Hun, Song, Hun Min, Lee, Jin Wook, Kim, Mi Kyoung, Lee, Man Hyo, Lee, Jeong Rak, Koo, Jin Suk, Jeong, Jin Boo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2015
• Subjects: Antineoplastic Agents - pharmacology; Cancer chemoprevention; Cell Cycle - drug effects; Cell growth; Cell Proliferation - drug effects; Colorectal Neoplasms - metabolism; Cyclin D1; Cyclin D1 - genetics; Cyclin D1 - metabolism; HCT116 Cells; Human colorectal cancer; Humans; Leupeptins - pharmacology; NF-kappa B - antagonists & inhibitors; Nitriles - pharmacology; Phosphorylation - drug effects; Point Mutation - genetics; Proteasome Endopeptidase Complex - drug effects; Proteasome Endopeptidase Complex - metabolism; Proteolysis; Silybum marianum; Silymarin; Silymarin - pharmacology; Sulfones - pharmacology; Threonine - genetics; Threonine - metabolism; Cancer chemoprevention; Human colorectal cancer; Cell growth; Silymarin; Cyclin D1
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2014.11.009

Silymarin from milk thistle (Silybum marianum) plant has been reported to show anti-cancer, anti-inflammatory, antioxidant and hepatoprotective effects. For anti-cancer activity, silymarin is known to regulate cell cycle progression through cyclin D1 downregulation. However, the mechanism of silymarin-mediated cyclin D1 downregulation still remains unanswered. The current study was performed to elucidate the molecular mechanism of cyclin D1 downregulation by silymarin in human colorectal cancer cells. The treatment of silymarin suppressed the cell proliferation in HCT116 and SW480 cells and decreased cellular accumulation of exogenously-induced cyclin D1 protein. However, silymarin did not change the level of cyclin D1 mRNA. Inhibition of proteasomal degradation by MG132 attenuated silymarin-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with silymarin. In addition, silymarin increased phosphorylation of cyclin D1 at threonine-286 and a point mutation of threonine-286 to alanine attenuated silymarin-mediated cyclin D1 downregulation. Inhibition of NF-κB by a selective inhibitor, BAY 11-7082 suppressed cyclin D1 phosphorylation and downregulation by silymarin. From these results, we suggest that silymarin-mediated cyclin D1 downregulation may result from proteasomal degradation through its threonine-286 phosphorylation via NF-κB activation. The current study provides new mechanistic link between silymarin, cyclin D1 downregulation and cell growth in human colorectal cancer cells. •Silymarin inhibited the cell growth in human colon cancer cells.•Silymarin induced cyclin D1 proteasomal degradation via threonine-286 phosphorylation.•Silymarin-induced cyclin D1 proteasomal degradation was dependent on NF-κB activation.•These findings suggest that silymarin-induced cell growth arrest may be due to cyclin D1 downregulation.