Inducing apoptosis and enhancing chemosensitivity to Gemcitabine via RNA interference targeting Mcl-1 gene in pancreatic carcinoma cell

Autor: Huizhong Zhang, Xi Wang, Fang Lin, San-Hua Wei, Bin Li, Qing Zhang, Jian-Jun Shen, Rui Wang, Ke Dong
Rok vydání: 2008
Předmět:
Antimetabolites
Antineoplastic
Cancer Research
Pancreatic disease
Genetic Vectors
Molecular Sequence Data
Cell
Down-Regulation
Mice
Nude
Apoptosis
Adenocarcinoma
Biology
Toxicology
Deoxycytidine
Mice
Downregulation and upregulation
RNA interference
Cell Line
Tumor
hemic and lymphatic diseases
Pancreatic cancer
medicine
Animals
Humans
Gene silencing
Pharmacology (medical)
RNA
Small Interfering
Tumor Stem Cell Assay
Pharmacology
Gene knockdown
Base Sequence
Cell growth
Cell Cycle
Inverted Repeat Sequences
medicine.disease
Xenograft Model Antitumor Assays
Gemcitabine
Neoplasm Proteins
Specific Pathogen-Free Organisms
Pancreatic Neoplasms
medicine.anatomical_structure
Proto-Oncogene Proteins c-bcl-2
Oncology
Drug Resistance
Neoplasm
Gene Knockdown Techniques
Cancer research
Myeloid Cell Leukemia Sequence 1 Protein
RNA Interference
Zdroj: Cancer Chemotherapy and Pharmacology. 62:1055-1064
ISSN: 1432-0843
0344-5704
DOI: 10.1007/s00280-008-0697-7
Popis: 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.
Databáze: OpenAIRE
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