Inducing apoptosis and enhancing chemosensitivity to Gemcitabine via RNA interference targeting Mcl-1 gene in pancreatic carcinoma cell
- 480 Downloads
Resistance to chemotherapy is a major cause of treatment failure and poor prognosis in pancreatic carcinoma. Myeloid cell leukemia-1 (Mcl-1) is highly up-regulated in pancreatic carcinoma and is associated with the anti-apoptosis and the resistance to chemotherapy drugs. Suppression of Mcl-1 would be an approach to induce apoptosis and enhance the chemosensitivity.
In this study, three pancreatic cancer cell lines (PANC-1, BxPC-3 and SW1900) stably expressing shRNAs targeting Mcl-1 gene were established and gene expression inhibition was assessed by Real-Time QPCR and Western blotting. The effects of Mcl-1 downregulation mediated by RNAi were explored in vitro and in vivo.
We showed that the specific downregulation of Mcl-1 strikingly inhibited cell growth, colony formation, cell cycle arrest and induced apoptosis in pancreatic cancer cells in vitro, and markedly decreased the tumorigenicity in a mouse xenograft model. Moreover, knockdown of Mcl-1 significantly increased the chemosensitivity to Gemcitabine in pancreatic carcinoma cells.
Our data suggests that the specific downregulation of Mcl-1 by RNAi is a promising approach to induce apoptosis and enhance the chemosensitivity for pancreatic carcinoma gene therapy.
KeywordsMcl-1 RNA interference Apoptosis Pancreatic carcinoma Chemotherapy
The research was supported by a grant from the Natural Science Foundation of Shaanxi Province (2003K10G44). Thanks to every one of department of clinical laboratory for their sincere help and technical support.
- 4.Evans DB, Abbruzzese JL, Rich TZ (1997) Cancer of the pancreas. In: DeVita VT, Hellman S, Rosenberg SA (eds) Cancer, principles and practice of oncology. 5th edn. J.B. Lippincott Co, Philadelphia, pp 1054–1087Google Scholar
- 7.Zelenin AV, Kaigrorodov VA, Prasdov VA (2000) Gene therapy today and tomorrow [J]. Mol Biol 32(2):188–196Google Scholar
- 14.Krajewski S, Bodrug S, Krajewska M, Shabaik A, Gascoyne R, Berean K, Reed JC (1995) Immunohistochemical analysis of Mcl-1 protein in human tissues. Differential regulation of Mcl-1 and Bcl-2 protein production suggests a unique role for Mcl-1 in control of programmed cell death in vivo. Am J Pathol 146(6):1309–1319PubMedGoogle Scholar
- 20.Hussain SR, Cheney CM, Johnson AJ, Lin TS, Grever MR, Caligiuri MA, Lucas DM, Byrd JC (2007) Mcl-1 is a relevant therapeutic target in acute and chronic lymphoid malignancies: down-regulation enhances rituximab-mediated apoptosis and complement-dependent cytotoxicity. Clin Cancer Res 13(7):2144–2150PubMedCrossRefGoogle Scholar
- 34.Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hott DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413PubMedGoogle Scholar
- 35.Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkhart C et al (2007) Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. J Am Med Assoc 297(3):267–277CrossRefGoogle Scholar