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HMGA1 Is a Molecular Determinant of Chemoresistance to Gemcitabine in Pancreatic Adenocarcinoma

Authors' Affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Edward E. Whang, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115. Phone: 617-7328669; Fax: 617-7391728; E-mail: ewhang1{at}partners.org.

Purpose: HMGA1 proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. We previously have shown that RNA interference targeting the HMGA1 gene may represent a potential chemosensitizing strategy in pancreatic adenocarcinoma cells. In this study, we tested the hypothesis that HMGA1 promotes chemoresistance to gemcitabine in pancreatic cancer cells.

Experimental Design and Results: Stable short hairpin RNA–mediated HMGA1 silencing in BxPC3 and MiaPaCa2 cells promoted chemosensitivity to gemcitabine, with reductions in gemcitabine IC₅₀ and increases in gemcitabine-induced apoptosis and caspase-3 activation. In contrast, forced HMGA1 overexpression in MiaPaCa2 cells promoted chemoresistance to gemcitabine, with increases in gemcitabine IC₅₀ and reductions in gemcitabine-induced apoptosis and caspase-3 activation. Dominant negative Akt abrogated HMGA1 overexpression–induced increases in chemoresistance to gemcitabine. Finally, HMGA1 silencing promoted chemosensitivity to gemcitabine in vivo in a nude mouse xenograft model of pancreatic adenocarcinoma.

Conclusion: Our findings suggest that HMGA1 promotes chemoresistance to gemcitabine through an Akt-dependent mechanism. Targeted therapies directed at HMGA1 represent a potential strategy for ameliorating chemoresistance in pancreatic adenocarcinoma.

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