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The role of Atg5 gene in tumorigenesis under autophagy deficiency conditions

Authors :
Hsiao‐Sheng Liu
Yin‐Ping Wang
Pei‐Wen Lin
Man‐Ling Chu
Sheng‐Hui Lan
Shan‐Ying Wu
Ying‐Ray Lee
Hong‐Yi Chang
Source :
Kaohsiung Journal of Medical Sciences, Vol 40, Iss 7, Pp 631-641 (2024)
Publication Year :
2024
Publisher :
Wiley, 2024.

Abstract

Abstract Autophagy is a self‐recycling machinery to maintain cellular homeostasis by degrading harmful materials in the cell. Autophagy‐related gene 5 (Atg5) is required for autophagosome maturation. However, the role of Atg5 in tumorigenesis under autophagy deficient conditions remains unclear. This study focused on the autophagy‐independent role of Atg5 and the underlying mechanism in tumorigenesis. We demonstrated that knockout of autophagy‐related genes including Atg5, Atg7, Atg9, and p62 in mouse embryonic fibroblast (MEF) cells consistently decreased cell proliferation and motility, implying that autophagy is required to maintain diverse cellular functions. An Atg7 knockout MEF (Atg7−/− MEF) cell line representing deprivation of autophagy function was used to clarify the role of Atg5 transgene in tumorigenesis. We found that Atg5‐overexpressed Atg7−/‐MEF (clone A) showed increased cell proliferation, colony formation, and migration under autophagy deficient conditions. Accordingly, rescuing the autophagy deficiency of clone A by overexpression of Atg7 gene shifts the role of Atg5 from pro‐tumor to anti‐tumor status, indicating the dual role of Atg5 in tumorigenesis. Notably, the xenograft mouse model showed that clone A of Atg5‐overexpressed Atg7−/− MEF cells induced temporal tumor formation, but could not prolong further tumor growth. Finally, biomechanical analysis disclosed increased Wnt5a secretion and p‐JNK expression along with decreased β‐catenin expression. In summary, Atg5 functions as a tumor suppressor to protect the cell under normal conditions. In contrast, Atg5 shifts to a pro‐tumor status under autophagy deprivation conditions.

Details

Language :
English
ISSN :
24108650 and 1607551X
Volume :
40
Issue :
7
Database :
Directory of Open Access Journals
Journal :
Kaohsiung Journal of Medical Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.f842293ee22c4ac499453b39c2812390
Document Type :
article
Full Text :
https://doi.org/10.1002/kjm2.12853