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-kappaB 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-kappaB 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.
PURPOSE: Elevated cyclin D1 in humanpancreatic 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-kappaB 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-kappaB 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.
Authors: Jonathan F Wilkey; Glenn Buchberger; Kirsten Saucier; Salony M Patel; Ellen Eisenberg; Hiroshi Nakagawa; Carmen Z Michaylira; Anil K Rustgi; Sanjay M Mallya Journal: Mol Carcinog Date: 2009-09 Impact factor: 4.784
Authors: Min Li; Yuqing Zhang; Uddalak Bharadwaj; Qihui Jim Zhai; Charlotte H Ahern; William E Fisher; F Charles Brunicardi; Craig D Logsdon; Changyi Chen; Qizhi Yao Journal: Clin Cancer Res Date: 2009-09-15 Impact factor: 12.531
Authors: Elizabeth A Musgrove; C Elizabeth Caldon; Jane Barraclough; Andrew Stone; Robert L Sutherland Journal: Nat Rev Cancer Date: 2011-07-07 Impact factor: 60.716
Authors: Lu Mei He; Daniel J Sartori; Monica Teta; Lynn M Opare-Addo; Matthew M Rankin; Simon Y Long; J Alan Diehl; Jake A Kushner Journal: Mol Endocrinol Date: 2009-07-23