c-Myc-induced chemosensitization is mediated by suppression of cyclin D1 expression and nuclear factor-κB activity in pancreatic cancer cells

Hector Biliran, Sanjeev Banerjee, Archana Thakur, Fazlul H. Sarkar, Aliccia Bollig, Fakhara Ahmed, Jiusheng Wu, Yuan Sun, Joshua D. Liao

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Purpose: Pancreatic cancer is a highly aggressive disease that remains refractory to various chemotherapeutic agents. Because the proto-oncogene c-myc can modulate apoptosis in response to cytotoxic insults and is commonly overexpressed in pancreatic cancer, we investigated the value of c-myc as a potential modulator of cellular response to various chemotherapeutic agents. Experimental Design: Stable overexpression or small interfering RNA (siRNA)-mediated knockdown of c-myc and restoration of cyclin D1 were done in the Ela-myc pancreatic tumor cell line. Cell viability after cisplatin treatment of c-myc - overexpressing, control, and siRNA-transfected cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and drug-induced apoptosis was measured by DNA fragmentation, sub-G-1, and poly(ADP-ribose) polymerase cleavage analyses. Protein expression profile after cisplatin treatment was determined by Western blotting and DNA binding activity of nuclear factor-κB was examined by electrophoretic mobility shift assay. Results: Ectopic overexpression of c-myc in murine and human pancreatic cancer cell lines, Ela-myc and L3.6pl, respectively, resulted in increased sensitivity to cisplatin and other chemotherapeutic drugs. Increased sensitivity to cisplatin in c-myc - overexpressing cells was due, in part, to the marked increase in cisplatin-induced apoptosis. Conversely, down-regulation of c-myc expression in stable c-myc - overexpressing cells by c-myc siRNA resulted in decreased sensitivity to cisplatin-induced cell death. These results indicate an important role of c-myc in chemosensitivity of pancreatic cancer cells. The c-myc - induced cisplatin sensitivity correlated with inhibition of nuclear factor κB activity, which was partially restored by ectopic cyclin D1 overexpression. Conclusions: Our results suggest that the c-myc - dependent sensitization to chemotherapy-induced apoptosis involves suppression of cyclin D1 expression and nuclear factor κB activity.

Original languageEnglish (US)
Pages (from-to)2811-2821
Number of pages11
JournalClinical Cancer Research
Volume13
Issue number9
DOIs
StatePublished - May 1 2007

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