Open AccessInhibition of acid ceramidase elicits mitochondrial dysfunction and oxidative stress in pancreatic cancer cells
Author(s) -
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
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15123
Subject(s) - pancreatic cancer , ceramide , apoptosis , cancer cell , reactive oxygen species , cancer research , oxidative stress , small hairpin rna , cancer , mitochondrion , chemistry , biology , pharmacology , biochemistry , genetics , gene knockdown
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.