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Rottlerin induces pro-apoptotic endoplasmic reticulum stress through the protein kinase C-δ-independent pathway in human colon cancer cells

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Abstract

Rottlerin, a compound reported to be a PKC δ-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-2α (eIF-2α), 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 δ expression by siRNA or overexpression of WT-PKC δ and DN-PKC δ did not abrogate the rottlerin-mediated induction of CHOP. These results suggest that rottlerin induces up-regulation of CHOP via PKC δ-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.

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Acknowledgements

This work was supported by research program of dual regulation mechanisms of aging and cancer from KOSEF (M1075604000107N560400110), and MRC at Keimyung University (R13-2002-028-01002-0), and funded by the Korean Government (MOEHRD) (KRF-2007-355-C00050), and Korea Research Foundation Grant KRF-2005-070-C00100.

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Authors and Affiliations

  1. 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

    Jun Hee Lim, Jong-Wook Park & Taeg Kyu Kwon

  2. Department of Pharmacology, School of Medicine, Kyungpook National University, Taegu, 700-422, South Korea

    Sang Hyun Kim

  3. Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, South Korea

    Yung Hyun Choi

  4. Institute for Medical Sciences, Ajou University School of Medicine, 5 Woncheon-Dong, Paldal-Gu, Suwon, 442-749, South Korea

    Kyeong Sook Choi

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  1. Jun Hee Lim
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Correspondence to Taeg Kyu Kwon.

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Lim, J.H., Park, JW., Kim, S.H. et al. Rottlerin induces pro-apoptotic endoplasmic reticulum stress through the protein kinase C-δ-independent pathway in human colon cancer cells. Apoptosis 13, 1378–1385 (2008). https://doi.org/10.1007/s10495-008-0264-z

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