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Suppression of lysosomal acid alpha‐glucosidase impacts the modulation of transcription factor EB translocation in pancreatic cancer
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 therapeu...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177769/ https://www.ncbi.nlm.nih.gov/pubmed/33931930 http://dx.doi.org/10.1111/cas.14921 |
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author | Hamura, Ryoga Shirai, Yoshihiro Shimada, Yohta Saito, Nobuhiro Taniai, Tomohiko Horiuchi, Takashi Takada, Naoki Kanegae, Yumi Ikegami, Toru Ohashi, Toya Yanaga, Katsuhiko |
author_facet | Hamura, Ryoga Shirai, Yoshihiro Shimada, Yohta Saito, Nobuhiro Taniai, Tomohiko Horiuchi, Takashi Takada, Naoki Kanegae, Yumi Ikegami, Toru Ohashi, Toya Yanaga, Katsuhiko |
author_sort | Hamura, Ryoga |
collection | PubMed |
description | 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 (siGAA) 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. |
format | Online Article Text |
id | pubmed-8177769 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-81777692021-06-15 Suppression of lysosomal acid alpha‐glucosidase impacts the modulation of transcription factor EB translocation in pancreatic cancer Hamura, Ryoga Shirai, Yoshihiro Shimada, Yohta Saito, Nobuhiro Taniai, Tomohiko Horiuchi, Takashi Takada, Naoki Kanegae, Yumi Ikegami, Toru Ohashi, Toya Yanaga, Katsuhiko Cancer Sci Original Articles 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 (siGAA) 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. John Wiley and Sons Inc. 2021-05-03 2021-06 /pmc/articles/PMC8177769/ /pubmed/33931930 http://dx.doi.org/10.1111/cas.14921 Text en © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Hamura, Ryoga Shirai, Yoshihiro Shimada, Yohta Saito, Nobuhiro Taniai, Tomohiko Horiuchi, Takashi Takada, Naoki Kanegae, Yumi Ikegami, Toru Ohashi, Toya Yanaga, Katsuhiko Suppression of lysosomal acid alpha‐glucosidase impacts the modulation of transcription factor EB translocation in pancreatic cancer |
title | Suppression of lysosomal acid alpha‐glucosidase impacts the modulation of transcription factor EB translocation in pancreatic cancer |
title_full | Suppression of lysosomal acid alpha‐glucosidase impacts the modulation of transcription factor EB translocation in pancreatic cancer |
title_fullStr | Suppression of lysosomal acid alpha‐glucosidase impacts the modulation of transcription factor EB translocation in pancreatic cancer |
title_full_unstemmed | Suppression of lysosomal acid alpha‐glucosidase impacts the modulation of transcription factor EB translocation in pancreatic cancer |
title_short | Suppression of lysosomal acid alpha‐glucosidase impacts the modulation of transcription factor EB translocation in pancreatic cancer |
title_sort | suppression of lysosomal acid alpha‐glucosidase impacts the modulation of transcription factor eb translocation in pancreatic cancer |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177769/ https://www.ncbi.nlm.nih.gov/pubmed/33931930 http://dx.doi.org/10.1111/cas.14921 |
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