title: Silymarin induces cyclin D1 proteasomal degradation via its phosphorylation of threonine-286 in human colorectal cancer cells.
abstract: 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.
authors.affiliation: Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea.
authors.forename: Hyun Ji
authors.initials: HJ
authors.lastname: Eo
authors.affiliation: Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea.
authors.forename: Gwang Hun
authors.initials: GH
authors.lastname: Park
authors.affiliation: Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea.
authors.forename: Hun Min
authors.initials: HM
authors.lastname: Song
authors.affiliation: Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea.
authors.forename: Jin Wook
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea.
authors.forename: Mi Kyoung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Gyeongbuk Institute for Bio-industry, Andong 760380, Republic of Korea.
authors.forename: Man Hyo
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Gyeongbuk Institute for Bio-industry, Andong 760380, Republic of Korea.
authors.forename: Jeong Rak
authors.initials: JR
authors.lastname: Lee
authors.affiliation: Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea; Institute of Agricultural Science and Technology, Andong National University, Andong 760749, Republic of Korea.
authors.forename: Jin Suk
authors.initials: JS
authors.lastname: Koo
authors.affiliation: Department of Bioresource Sciences, Andong National University, Andong 760749, Republic of Korea; Institute of Agricultural Science and Technology, Andong National University, Andong 760749, Republic of Korea. Electronic address: jjb0403@anu.ac.kr.
authors.forename: Jin Boo
authors.initials: JB
authors.lastname: Jeong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D020944:Silybum marianum; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017354:Point Mutation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D059748:Proteolysis; D012838:Silymarin / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D013912:Threonine / Q000235:genetics / Q000378:metabolism
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; D007976:Leupeptins; D016328:NF-kappa B; D009570:Nitriles; D012838:Silymarin; D013450:Sulfones; D019938:Cyclin D1; D013912:Threonine; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Cancer chemoprevention; Cell growth; Cyclin D1; Human colorectal cancer; Silymarin