This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Biliran, H. Articles by Liao, J. D. Search for Related Content PubMed PubMed Citation Articles by Biliran, H., Jr. Articles by Liao, J. D.

Overexpression of Cyclin D1 Promotes Tumor Cell Growth and Confers Resistance to Cisplatin-Mediated Apoptosis in an Elastase-myc Transgene–Expressing Pancreatic Tumor Cell Line

Authors' Affiliations: ¹ Department of Pathology and ² Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan

Requests for reprints: Joshua D. Liao, Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201. Phone: 313-966-9376; Fax: 313-966-7558; E-mail: dliao{at}med.wayne.edu.

Purpose: Elevated cyclin D1 in human pancreatic cancer correlates with poor prognosis. Because pancreatic cancer is invariably resistant to chemotherapy, the goal of this study was to examine whether the drug resistance of pancreatic cancer cells is in part attributed to cyclin D1 overexpression.

Experimental Design: Stable overexpression and small interfering RNA (siRNA)–mediated knockdown of cyclin D1 were done in the newly established Ela-myc pancreatic tumor cell line. Cisplatin sensitivity of control, overexpressing, and siRNA-transfected cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, clonogenic, and apoptotic assays [DNA fragmentation, sub-G₁, and poly(ADP-ribose) polymerase cleavage analysis]. The role of nuclear factor-B and apoptotic proteins in cyclin D1-mediated chemoresistance was examined by EMSA and Western blotting, respectively.

Results: Overexpression of cyclin D1 in Ela-myc pancreatic tumor cells promoted cell proliferation and anchorage-independent growth. Moreover, cyclin D1–overexpressing cells exhibited significantly reduced chemosensitivity and a higher survival rate upon cisplatin treatment, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and clonogenic assays, respectively. Although overexpression of cyclin D1 rendered cells more resistant to cisplatin-induced apoptosis, siRNA-directed suppression of cyclin D1 expression resulted in enhanced susceptibility to cisplatin-mediated apoptosis. The attenuation of cisplatin-induced cell death in cyclin D1–overexpressing cells was correlated with the up-regulation of nuclear factor-B activity and maintenance of bcl-2 and bcl-xl protein levels.

Conclusions: These results suggest that overexpression of cyclin D1 can contribute to chemoresistance of pancreatic cancer cells because of the dual roles of cyclin D1 in promoting cell proliferation and in inhibiting drug-induced apoptosis.

This article has been cited by other articles:

				M. T. Yip-Schneider, H. Wu, M. Ralstin, C. Yiannoutsos, P. A. Crooks, S. Neelakantan, S. Noble, H. Nakshatri, C. J. Sweeney, and C. M. Schmidt Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibition in vivo Mol. Cancer Ther., June 1, 2007; 6(6): 1736 - 1744. [Abstract] [Full Text] [PDF]

				S. Michienzi, B. Bucci, C. Verga Falzacappa, V. Patriarca, A. Stigliano, L. Panacchia, E. Brunetti, V. Toscano, and S. Misiti 3,3',5-Triiodo-L-thyronine inhibits ductal pancreatic adenocarcinoma proliferation improving the cytotoxic effect of chemotherapy J. Endocrinol., May 1, 2007; 193(2): 209 - 223. [Abstract] [Full Text] [PDF]

				H. Biliran Jr., S. Banerjee, A. Thakur, F. H. Sarkar, A. Bollig, F. Ahmed, J. Wu, Y. Sun, and J. D. Liao c-Myc Induced Chemosensitization Is Mediated by Suppression of Cyclin D1 Expression and Nuclear Factor-{kappa}B Activity in Pancreatic Cancer Cells Clin. Cancer Res., May 1, 2007; 13(9): 2811 - 2821. [Abstract] [Full Text] [PDF]

				H.-S. Shiah, W. Gao, D. C. Baker, and Y.-C. Cheng Inhibition of cell growth and nuclear factor-{kappa}B activity in pancreatic cancer cell lines by a tylophorine analogue, DCB-3503. Mol. Cancer Ther., October 1, 2006; 5(10): 2484 - 2493. [Abstract] [Full Text] [PDF]

				Z. Wang, R. Sengupta, S. Banerjee, Y. Li, Y. Zhang, K.M. W. Rahman, A. Aboukameel, R. Mohammad, A. P.N. Majumdar, J. L. Abbruzzese, et al. Epidermal growth factor receptor-related protein inhibits cell growth and invasion in pancreatic cancer. Cancer Res., August 1, 2006; 66(15): 7653 - 7660. [Abstract] [Full Text] [PDF]

				J. A. Diehl and S. Benzeno Cyclin D1 and Pancreatic Carcinoma: A Proliferative Agonist and Chemotherapeutic Antagonist Clin. Cancer Res., August 15, 2005; 11(16): 5665 - 5667. [Full Text] [PDF]