Inhibition of acid ceramidase elicits mitochondrial dysfunction and oxidative stress in pancreatic cancer cells
Tomohiko Taniai, Yoshihiro Shirai, Yohta Shimada, Ryoga Hamura, Mitsuru Yanagaki, Naoki Takada, Takashi Horiuchi, Koichiro Haruki, Kenei Furukawa, Tadashi Uwagawa, Kazuhito Tsuboi, Yasuo Okamoto, Shu Shimada, Shinji Tanaka, Toya Ohashi, Toru Ikegami
Abstract
Although the inhibition of acid ceramidase (AC) is known to induce antitumor effects in various cancers, there are few reports in pancreatic cancer, and the underlying mechanisms remain unclear. Moreover, there is currently no safe administration method of AC inhibitor. Here the effects of gene therapy using siRNA and shRNA for AC inhibition with its mechanisms for pancreatic cancer were investigated. The inhibition of AC by siRNA and shRNA using an adeno-associated virus 8 (AAV8) vector had antiproliferative effects by inducing apoptosis in pancreatic cancer cells and xenograft mouse model. Acid ceramidase inhibition elicits mitochondrial dysfunction, reactive oxygen species accumulation, and manganese superoxide dismutase suppression, resulting in apoptosis of pancreatic cancer cells accompanied by ceramide accumulation. These results elucidated the mechanisms underlying the antitumor effect of AC inhibition in pancreatic cancer cells and suggest the potential of the AAV8 vector to inhibit AC as a therapeutic strategy.