title: Rottlerin induces apoptosis of HT29 colon carcinoma cells through NAG-1 upregulation via an ERK and p38 MAPK-dependent and PKC δ-independent mechanism.
abstract: Rottlerin, a selective inhibitor of novel isoforms of protein kinase C δ (PKC δ), has been shown to exert multiple effects on cancer cells, including inhibition of cell proliferation and migration. However, the molecular mechanisms responsible for these effects are not fully understood. We found that rottlerin dramatically induced non-steroidal anti-inflammatory drug activated gene-1 (NAG-1) expression in both p53 wild-type and p53-null cancer cell lines, suggesting that NAG-1 upregulation is a common response to rottlerin that occurs independently of p53 in multiple cell lines. Although rottlerin is known to inhibit PKC δ, PKC δ siRNA and overexpression of dominant-negative (DN)-PKC δ did not affect rottlerin-mediated induction of NAG-1. These results suggest that rottlerin induces NAG-1 upregulation via a PKC δ-independent pathway. We also observed that CHOP protein levels were significantly increased by rottlerin, but CHOP siRNA did not affect rottlerin-induced NAG-1 expression. In addition, we demonstrated the involvement of the mitogen-activated protein kinase (MAP kinase) signal transduction pathway in rottlerin-induced NAG-1 expression. Inhibitors of MEK (PD98059) and p38 MAP kinase (SB203580) prevented rottlerin-induced NAG-1 expression. Furthermore, we found that down-regulation of NAG-1 attenuated rottlerin-induced apoptosis. Collectively, the results of this study demonstrate, for the first time, that upregulation of NAG-1 contributes to rottlerin-induced apoptosis in cancer cells.
authors.affiliation: Department of Immunology, School of Medicine, Keimyung University, Dalseo-Gu, Daegu, Republic of Korea.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lim
authors.forename: Seon Min
authors.initials: SM
authors.lastname: Woo
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Min
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jang
authors.forename: Bo Ram
authors.initials: BR
authors.lastname: Seo
authors.forename: Taha
authors.initials: T
authors.lastname: Iqbal
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Lee
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017353:Gene Deletion; D055436:Growth Differentiation Factor 15 / Q000235:genetics* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D051745:Protein Kinase C-delta / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051742:Transcription Factor CHOP / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; C497249:DDIT3 protein, human; D004791:Enzyme Inhibitors; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051742:Transcription Factor CHOP; C085746:rottlerin; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases