Apoptosis induced by t10,c12-conjugated linoleic acid is mediated by an atypical endoplasmic reticulum stress response

Lihui Ou, Yue Wu, Clement Ip, Xiaojing Meng, Yung-Chun Hsu, and Margot M. Ip

Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263

Corresponding Author: margot.ip{at}roswellpark.org

CLA inhibits rat mammary carcinogenesis, in part by inducing apoptosis of preneoplastic and neoplastic mammary epithelial cells. The current study focused on the mechanism by which apoptosis is induced. In TM4t mammary tumor cells, t10,c12-CLA induced proapoptotic C/EBP-homologous protein (CHOP) concurrent with the cleavage of PARP. Knockdown of CHOP attenuated t10,c12-CLA-induced apoptosis. Furthermore, t10,c12-CLA induced cleavage of endoplasmic reticulum (ER)-resident caspase-12, and a selective inhibitor of caspase-12 significantly alleviated t10,c12-CLA-induced apoptosis. Using electron microscopy, we observed that t10,c12-CLA treatment resulted in marked dilatation of the ER lumen. Together, these data suggest that t10,c12-CLA induces apoptosis through ER stress. To further explore the ER stress pathway, we examined the expression of the following upstream ER stress signature markers in response to CLA treatment: XBP1 mRNA (unspliced and spliced); phospho-eIF2a, ATF4 and BiP proteins. We found that t10,c12-CLA induced expression and splicing of XBP1 mRNA, as well as phosphorylation of eIF2a. In contrast, ATF4 was induced modestly, but not significantly, and BiP was not altered. In summary, our data demonstrate that apoptosis induced by t10,c12-CLA is mediated, at least in part, through an atypical ER stress response that culminates in the induction of CHOP and cleavage of caspase-12.

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