Suppression of lysosomal acid alpha‐glucosidase impacts the modulation of transcription factor EB translocation in pancreatic cancer. Issue 6 (3rd May 2021)

• Record Type: Journal Article
• Authors: Hamura, Ryoga; Shirai, Yoshihiro; Shimada, Yohta; Saito, Nobuhiro; Taniai, Tomohiko; Horiuchi, Takashi; Takada, Naoki; Kanegae, Yumi; Ikegami, Toru; Ohashi, Toya; Yanaga, Katsuhiko
• Is Part Of: Cancer science. Volume 112:Issue 6(2021)
• Page Start: 2335
• Page End: 2348
• Publication Date: 2021-05-03
• Subjects: GAA -- gene therapy -- lysosome -- pancreatic cancer -- TFEB translocation; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14921
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Lysosomal degradation plays a crucial role in the metabolism of biological macromolecules supplied by autophagy. The regulation of the autophagy‐lysosome system, which contributes to intracellular homeostasis, chemoresistance, and tumor progression, has recently been revealed as a promising therapeutic approach for pancreatic cancer (PC). However, the details of lysosomal catabolic function in PC cells have not been fully elucidated. In this study, we show evidence that suppression of acid alpha‐glucosidase (GAA), one of the lysosomal enzymes, improves chemosensitivity and exerts apoptotic effects on PC cells through the disturbance of expression of the transcription factor EB. The levels of lysosomal enzyme were elevated by gemcitabine in PC cells. In particular, the levels of GAA were responsive to gemcitabine in a dose–dependent and time–dependent manner. Small interfering RNA against the GAA gene (si GAA ) suppressed cell proliferation and promoted apoptosis in gemcitabine‐treated PC cells. In untreated PC cells, we observed accumulation of depolarized mitochondria. Gene therapy using adenoviral vectors carrying shRNA against the GAA gene increased the number of apoptotic cells and decreased the tumor growth in xenograft model mice. These results indicate that GAA is one of the key targets to improve the efficacy of gemcitabine and develop novel therapies for PC. Abstract : In this study, we demonstrated that enhancement of lysosomal activity with gemcitabine was involved in resistance to treatment in PC cells. Furthermore, suppression of GAA, a lysosomal enzyme, improves the sensitivity to gemcitabine and induces apoptosis in PC cells through modulation of TFEB translocation.