Up-regulation of integrin beta3 in radioresistant pancreatic cancer impairs adenovirus-mediated gene therapy.
Adenovirus-mediated gene therapy is a promising approach for the treatment of pancreatic cancer. We previously reported that radiation enhanced adenovirus-mediated gene expression in pancreatic cancer, suggesting that adenoviral gene therapy might be more effective in radioresistant pancreatic cancer cells. In the present study, we compared the transduction efficiency of adenovirus-delivered genes in radiosensitive and radioresistant cells, and investigated the underlying mechanisms. We used an adenovirus expressing the hepatocyte growth factor antagonist, NK4 (Ad-NK4), as a representative gene therapy. We established two radioresistant human pancreatic cancer cell lines using fractionated irradiation. Radiosensitive and radioresistant pancreatic cancer cells were infected with Ad-NK4, and NK4 levels in the cells were measured. In order to investigate the mechanisms responsible for the differences in the transduction efficiency between these cells, we measured expression of the genes mediating adenovirus infection and endocytosis. The results revealed that NK4 levels in radioresistant cells were significantly lower (P < 0.01) than those in radiosensitive cells, although there were no significant differences in adenovirus uptake between radiosensitive cells and radioresistant cells. Integrin beta3 was up-regulated and the Coxsackie virus and adenovirus receptor was down-regulated in radioresistant cells, and inhibition of integrin beta3 promoted adenovirus gene transfer. These results suggest that inhibition of integrin beta3 in radioresistant pancreatic cancer cells could enhance adenovirus-mediated gene therapy.
Egami
Takuya
T
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Ohuchida
Kenoki
K
Yasui
Takaharu
T
Mizumoto
Kazuhiro
K
Onimaru
Manabu
M
Toma
Hiroki
H
Sato
Norihiro
N
Matsumoto
Kunio
K
Tanaka
Masao
M
D000256:Adenoviridae / Q000235:genetics*; D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D011836:Radiation Tolerance / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D015854:Up-Regulation
C066855:HGF protein, human; D039661:Integrin beta3; D017228:Hepatocyte Growth Factor