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J. Biol. Chem., Vol. 281, Issue 42, 31440-31447, October 20, 2006

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Proteasome Inhibitor PS-341 Induces Apoptosis in Cisplatin-resistant Squamous Cell Carcinoma Cells by Induction of Noxa^*

Andrew M. Fribley, Benjamin Evenchik, Qinghua Zeng, Bae Keun Park, Jean Y. Guan, Honglai Zhang, Timothy J. Hale, Maria S. Soengas^¶, Randal J. Kaufman^||, and Cun-Yu Wang¹

From the Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, School of Dentistry, the Department of Epidemiology, School of Public Health, and the ^¶Department of Dermatology and Cancer Center, ^||Howard Hughes Medical Institution and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109

Cisplatin is one of the most common DNA-damaging agents used for treating patients with solid tumors such as squamous cell carcinoma (SCC). Unfortunately, significant levels of resistance in SCC cells emerge rapidly following cisplatin treatment. Here we report that the proteasome inhibitor PS-341, the representative of a new class of chemotherapeutic drugs, was capable of inducing apoptosis in cisplatin-resistant SCC cells via the endoplasmic reticulum stress. PS-341 stimulated the phosphorylation of PERK and the unfolded protein response, resulting in the induction of the transcription factor ATF-4. Importantly, the Bcl-2 homology domain 3-only (BH3-only) protein Noxa was found to be strongly induced in cisplatin-resistant SCC cells by PS-341 but not by cisplatin. The knock-down of Noxa using small interference RNA significantly abolished PS-341-mediated apoptosis in SCC cells. Using eIF2 mutant mouse embryonic fibroblasts, we found that functional eIF2 played an essential role in PS-341-induced Noxa expression. Taken together, our novel findings reveal a direct link between PS-341-induced endoplasmic reticulum stress and the mitochondria-dependent apoptotic pathway and suggest that PS-341 may be utilized for overcoming cisplatin-resistance in human SCC.

Received for publication, May 8, 2006 , and in revised form, August 22, 2006.

^* This study was supported by National Institutes of Health Grants R01DE013848 and R01DE15964 (to C.-Y. W.) and T32-DE0757 (to A. M. F.). 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 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Laboratory of Molecular Signaling and Apoptosis, Dept. of Biologic and Materials Sciences, University of Michigan, 1011 N. University Ave., Ann Arbor, MI 48109-1078. Tel.: 734-615-4386; Fax: 734-647-2110; E-mail: cunywang{at}umich.edu.

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