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.
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