Proteotoxic Stress Triggers Autophagy-Mediated AS160 Degradation and Metabolic Reprogramming in Colorectal Cancer
Issued Date
2026-05-05
Resource Type
eISSN
24701343
Scopus ID
2-s2.0-105037829396
Journal Title
ACS Omega
Volume
11
Issue
17
Start Page
25701
End Page
25711
Rights Holder(s)
SCOPUS
Bibliographic Citation
ACS Omega Vol.11 No.17 (2026) , 25701-25711
Suggested Citation
Reabroi S., Sutjarit N., Chairoungdua A. Proteotoxic Stress Triggers Autophagy-Mediated AS160 Degradation and Metabolic Reprogramming in Colorectal Cancer. ACS Omega Vol.11 No.17 (2026) , 25701-25711. 25711. doi:10.1021/acsomega.6c00543 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/116710
Title
Proteotoxic Stress Triggers Autophagy-Mediated AS160 Degradation and Metabolic Reprogramming in Colorectal Cancer
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Corresponding Author(s)
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Abstract
AS160 (TBC1D4) is a key regulator of glucose transporter trafficking and is frequently overexpressed in several malignancies. However, the mechanisms regulating its protein stability and its contribution to colon tumor metabolism remain poorly understood. Here, we identify a proteotoxic stress-responsive mechanism regulating AS160 abundance that involves crosstalk between the ubiquitin-proteasome system (UPS), ER stress-related signaling, and autophagy. Paradoxically, proteasome inhibition with MG132 resulted in a dose-dependent reduction of AS160 protein levels in both HCT116 and HT29 colon cancer cells, accompanied by the induction of ER stress markers and autophagy activation, including p62 accumulation and increased LC3-II/LC3-I ratios. In contrast, blockade of lysosomal degradation with chloroquine (CHQ) led to marked AS160 accumulation, suggesting that autophagy drives AS160 turnover under proteotoxic stress. Alleviating ER stress with 4-phenylbutyric acid (4-PBA) or scavenging reactive oxygen species with N-acetylcysteine (NAC) did not prevent AS160 loss following MG132 treatment. Functionally, shRNA-mediated knockdown of AS160 did not significantly alter glucose uptake or total GLUT1 protein levels; however, it increased lactate secretion accompanied by reciprocal changes in lactate transporters including upregulation of the lactate transporter MCT4 and downregulation of MCT1. Overall, our results suggest that the stability of AS160 protein is regulated through autophagy-associated pathways and that reduced AS160 expression is associated with altered lactate handling. Targeting pathways that regulate AS160 stability may therefore represent a strategy to modulate tumor metabolic adaptation.