Suppression of lysosomal acid alpha‐glucosidase impacts the modulation of transcription factor EB translocation in pancreatic cancer

Autor: Yumi Kanegae, Tomohiko Taniai, Nobuhiro Saito, Ryoga Hamura, Naoki Takada, Yohta Shimada, Toya Ohashi, Katsuhiko Yanaga, Yoshihiro Shirai, Takashi Horiuchi, Toru Ikegami
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
Cancer Research
Small interfering RNA
Time Factors
Cell Survival
pancreatic cancer
Mice
Nude
Deoxycytidine
Small hairpin RNA
Mice
03 medical and health sciences
0302 clinical medicine
Cell
Molecular
and Stem Cell Biology
Cell Line
Tumor
Lysosome
Autophagy
medicine
Animals
GAA
RNA
Small Interfering
Cell Proliferation
Dose-Response Relationship
Drug
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Chemistry
Cell growth
alpha-Glucosidases
Original Articles
General Medicine
Xenograft Model Antitumor Assays
Gemcitabine
gene therapy
Up-Regulation
Cell biology
Gene Expression Regulation
Neoplastic
Pancreatic Neoplasms
TFEB translocation
030104 developmental biology
medicine.anatomical_structure
Oncology
Drug Resistance
Neoplasm
Tumor progression
030220 oncology & carcinogenesis
lysosome
Acid alpha-glucosidase
TFEB
Original Article
Lysosomes
Zdroj: Cancer Science
ISSN: 1349-7006
1347-9032
DOI: 10.1111/cas.14921
Popis: 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.
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.
Databáze: OpenAIRE
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