Inhibition of acid ceramidase elicits mitochondrial dysfunction and oxidative stress in pancreatic cancer cells. Issue 11 (13th September 2021)

• Record Type: Journal Article
• Authors: Taniai, Tomohiko; Shirai, Yoshihiro; Shimada, Yohta; Hamura, Ryoga; Yanagaki, Mitsuru; Takada, Naoki; Horiuchi, Takashi; Haruki, Koichiro; Furukawa, Kenei; Uwagawa, Tadashi; Tsuboi, Kazuhito; Okamoto, Yasuo; Shimada, Shu; Tanaka, Shinji; Ohashi, Toya; Ikegami, Toru
• Is Part Of: Cancer science. Volume 112:Issue 11(2021)
• Page Start: 4570
• Page End: 4579
• Publication Date: 2021-09-13
• Subjects: acid ceramidase -- adeno‐associated virus -- mitochondrial dysfunction -- oxidative stress -- pancreatic ductal adenocarcinoma; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.15123
• Languages: English
• ISSNs: 1347-9032

Abstract

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. Abstract : 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. The current study 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.