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Departments of ¹ Medical Oncology and Therapeutic Research and ² Immunology, City of Hope National Medical Center, Duarte, California and ³ Department of Molecular Pharmacology and Toxicology and ⁴ Norris Cancer Center, University of Southern California, Los Angeles, California

Requests for reprints: Yun Yen, Department of Medical Oncology and Therapeutic Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010. Phone: 626-359-8111, ext. 62307; Fax: 626-301-8233. E-mail: yyen{at}coh.org

Bortezomib, a novel dipeptide boronic acid proteasome inhibitor, has been shown in previous studies to be synergistic with gemcitabine; however, the molecular mechanisms are not fully understood. Because post-translational modification of proteins, such as ubiquitination and SUMOylation, plays a critical role in governing cellular homeostasis, we explored this further by treating human oropharyngeal carcinoma KB wild-type (KBwt) and gemcitabine-resistant (KBGem) cells with gemcitabine and bortezomib in a time-dependent and sequence-dependent manner. Treatment with bortezomib at 4 to 8 hours post-gemcitabine significantly induced cell death in KBwt cell lines. However, in KBGem cells, bortezomib alone was just as cytotoxic. Using reporter assays, nuclear factor-B (NF-B) activity was found to be 5-fold higher in KBGem cells than that in KBwt cells, and the combination treatment decreased NF-B activity by 44% in KBwt cells and 28% in KBGem cells, respectively. By Western blot analyses, treatment with gemcitabine and bortezomib resulted in a cleavage of NF-B in KBwt but not in KBGem cells. SUMOylation capacity was modulated by transducing KBwt and KBGem cells with lenti-SUMO-1 or the unconjugatable lenti-SUMO-1aa followed by drug treatment. The expression of cyclins A, D1, and E was differentially regulated by SUMOylation capacity in KBGem but not in KBwt cells. We report herein that the activation of NF-B signaling plays a critical role in eliciting KBwt cell survival against gemcitabine, whereas the role of SUMOylation in modulating the steady-state levels of key cell cycle regulator proteins seems more significant in KBGem cells. [Mol Cancer Ther 2006;5(3):533–40]

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⁵ L.M. Boo and D.K. Ann, unpublished observation, 2005.

Received 8/ 1/05; revised 12/13/05; accepted 1/10/06.