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Departments of ¹ Cancer Chemoprevention and ² Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York USA

Requests for reprints: Clement Ip, Department of Cancer Chemoprevention, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8875; Fax: 716-845-8100. E-mail: clement.ip{at}roswellpark.org

Previously, -tocopheryl succinate (-TOS) has been reported to induce caspase-mediated apoptosis in PC-3 human prostate cancer cells. Caspase-9 was among several initiator caspases activated by -TOS, suggesting a potential contribution of the intrinsic apoptotic pathway in mediating the response to -TOS. Gene expression microarray was carried out as a screen to identify novel signaling molecules modulated by -TOS, with a special focus on those known to play a role in mitochondria-mediated apoptosis. We discovered that Ask1, GADD45ß, and Sek1, three key components of the stress-activated mitogen-activated protein kinase pathway, are novel targets of -TOS. Western blot analysis showed increased levels of phospho-Sek1 and phospho-c-Jun-NH₂-kinase (JNK) in addition to total Ask1, GADD45ß, and Sek1. -TOS also altered JNK-specific phosphorylation of Bcl-2 and Bim in a manner consistent with enhanced mitochondrial translocation of Bax and Bim. Because the expression level of most Bcl-2 family members remained unchanged, the posttranslational modification of Bcl-2 and Bim by JNK is likely to be a driving force in -TOS activation of the intrinsic apoptotic pathway. Based on our findings, we propose a working model to capture the salient features of the apoptotic signaling circuitry of -TOS.

Key Words: -tocopheryl succinate • apoptosis • mitochondrial pathway • JNK pathway • Bcl-2 family proteins

Grant support: Supported by grant CA 91990 from the NIC, and partially supported by core resources of the Roswell Park Cancer Institute Cancer Center support grant P30 CA 16056 from the National Cancer Institute.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with U.S.C. Section 1734 solely to indicate this fact.

Received 9/ 9/04; revised 10/29/04; accepted 11/ 8/04.