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Differential Regulation of Noxa in Normal Melanocytes and Melanoma Cells by Proteasome Inhibition: Therapeutic Implications

Departments of ¹ Dermatology, ² Chemistry, and ³ Obstetrics and Gynecology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan; ⁴ Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts; and ⁵ Cold Spring Harbor Laboratory, Cold Spring Harbor, New York

Requests for reprints: María S. Soengas, University of Michigan Comprehensive Cancer Center (4217 CCGC), 1500 East Medical Center Drive, Ann Arbor, MI 48109. Phone: 734-936-5643; Fax: 734-647-9654; E-mail: soengas{at}umich.edu.

Melanoma is the most aggressive form of skin cancer and advanced stages are invariably resistant to conventional therapeutic agents. Using bortezomib as a prototypic proteasome inhibitor, we have identified a novel and critical role of the proteasome in the maintenance of the malignant phenotype of melanoma cells that could have direct translational implications. Thus, melanoma cells from early, intermediate, and late stages of the disease could not sustain proteasome inhibition and underwent an effective activation of caspase-dependent and -independent death programs. This effect was tumor cell selective, because under similar conditions, normal melanocytes remained viable. Intriguingly, and despite of interfering with a cellular machinery in charge of controlling the half-life of the vast majority of cellular proteins, bortezomib did not promote a generalized disruption of melanoma-associated survival factors (including NF-B, Bcl-2, Bcl-x_L, XIAP, TRAF-2, or FLIP). Instead, we identified a dramatic induction in vitro and in vivo of the BH3-only protein Noxa in melanoma cells (but not in normal melanocytes) in response to proteasome inhibition. RNA interference validated a critical role of Noxa for the cytotoxic effect of bortezomib. Notably, the proteasome-dependent regulation of Noxa was found to extend to other tumor types, and it could not be recapitulated by standard chemotherapeutic drugs. In summary, our results revealed Noxa as a new biomarker to gauge the efficacy of bortezomib specifically in tumor cells, and provide a new strategy to overcome tumor chemoresistance.

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