title: Role of ASC in hypoxia-mediated cell death in pancreatic cancer.
abstract: ASC, an apoptosis-associated speck-like protein, can regulate apoptosis in response to various types of cell death stimuli. In this study, we investigated the role of ASC in hypoxia-mediated cell death in pancreatic cancer. ASC was inducible under a 1% O2 hypoxic condition in pancreatic cancer cells, which was HIF1α-dependent but p53-independent. Two representative chemotherapeutic agents for pancreatic cancer, 5-fluorouracil and gemcitabine, promoted cell death in a p53-dependent manner; however, 1% hypoxia caused chemoresistance to these drugs. Western blot analysis of this condition showed that expression of Bax, a pro-apoptotic gene, decreased, while the anti-apoptotic genes IAP-2 and survivin increased. These results suggest that, although hypoxia induces both pro-apoptotic and anti-apoptotic genes, the total balance seems to be anti-apoptotic dominant, which might explain chemoresistance in pancreatic cancer. To overcome this anti-apoptotic dominant condition, we infected adenovirus-expressing ASC into pancreatic cancer cells. The expressed ASC induced cell death even under 20% normoxia, and was enhanced by hypoxia. Our data demonstrate the possible mechanism of chemoresistance under hypoxia in pancreatic cancer cells, thereby suggesting the potential use of ASC as a new treatment strategy for pancreatic cancer.
authors.affiliation: Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan. ootsuka4@cc.saga-u.ac.jp.
authors.forename: Takao
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mitsuno
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kitajima
authors.forename: Takao
authors.initials: T
authors.lastname: Ide
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
authors.forename: Kohji
authors.initials: K
authors.lastname: Miyazaki