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Research Articles: Therapeutics, Targets, and Development

Chemosensitization of head and neck cancer cells by PUMA

¹ University of Pittsburgh Cancer Institute; Departments of ² Pathology, ³ Pharmacology, and ⁴ Otolaryngology, University of Pittsburgh School of Medicine; and ⁵ Department of Human Genetics, The University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania

Requests for reprints: Jian Yu, University of Pittsburgh Cancer Institute, Hillman Cancer Center Research Pavilion, Suite 2.26H, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-7786; Fax: 412-623-7778. E-mail: yuj2{at}upmc.edu

Abstract

Head and neck squamous cell carcinoma (HNSCC) ranks the eighth most common cancer worldwide. The patients often present with advanced disease, which responds poorly to chemoradiation therapy. PUMA is a BH3-only Bcl-2 family protein and a p53 target that is required for apoptosis induced by p53 and various chemotherapeutic agents. In this study, we found that PUMA induction by chemotherapeutic agents is abrogated in most HNSCC cell lines. Adenoviral gene delivery of PUMA induced apoptosis and chemosensitization more potently than did adenoviral delivery of p53 in HNSCC cells. Finally, we showed that PUMA suppressed the growth of HNSCC xenograft tumors and sensitized them to cisplatin through induction of apoptosis. Our data suggest that absence of PUMA activation in HNSCC cells contributes to chemoresistance and that gene therapy with PUMA might be an efficient substitute for p53 to enhance the responses of HNSCC cells to chemotherapy. [Mol Cancer Ther 2007;6(12):3180–8]

Grant support: Flight Attendant Medical Research Institute (FAMRI), the Alliance for Cancer Gene Therapy (ACGT), University of Pittsburgh Head and Neck SPORE grant (P50CA097190) career development award (J. Yu). SMG is supported in part by NIH R01DE014729 and University of Pittsburgh Head and Neck SPORE grant (P50CA97190).

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.

⁶ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 4/11/07; revised 9/13/07; accepted 10/ 9/07.

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