Rottlerin induces pro-apoptotic endoplasmic reticulum stress through the protein kinase C-delta-independent pathway in human colon cancer cells.
Rottlerin, a compound reported to be a PKC delta-selective inhibitor, has been shown to induce growth arrest or apoptosis of human cancer cell lines. In our study, rottlerin dose-dependently induced apoptotic cell death in colon carcinoma cells. Treatment of HT29 human colon carcinoma cells with rottlerin was found to induce a number of signature ER stress markers; phosphorylation of eukaryotic initiation factor-2alpha (eIF-2alpha), ER stress-specific XBP1 splicing, and up-regulation of glucose-regulated protein (GRP)-78 and CCAAT/enhancer-binding protein-homologous protein (CHOP). However, suppression of PKC delta expression by siRNA or overexpression of WT-PKC delta and DN-PKC delta did not abrogate the rottlerin-mediated induction of CHOP. These results suggest that rottlerin induces up-regulation of CHOP via PKC delta-independent pathway. Furthermore, down-regulation of CHOP expression using CHOP siRNA attenuated rottlerin-induced apoptosis. Taken together, the present study thus provides strong evidence to support an important role of ER stress response in mediating the rottlerin-induced apoptosis.
Lim
Jun Hee
JH
Department of Immunology, Chronic Disease Research Center, Institute for Medical Science, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea.
Park
Jong-Wook
JW
Kim
Sang Hyun
SH
Choi
Yung Hyun
YH
Choi
Kyeong Sook
KS
Kwon
Taeg Kyu
TK
D000098:Acetophenones / Q000494:pharmacology*; D017398:Alternative Splicing; D017209:Apoptosis; D001578:Benzopyrans / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D011489:Protein Denaturation; D051745:Protein Kinase C-delta / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; C085746:rottlerin; D051745:Protein Kinase C-delta