Docosahexaenoic acid promotes the formation of autophagosomes in MCF-7 breast cancer cells through oxidative stress-induced growth inhibitor 1 mediated activation of AMPK/mTOR pathway.

Abstract

Docosahexaenoic acid (DHA) is known to regulate autophagy in cancer cells. We explored whether oxidative stress-induced growth inhibitor 1 (OSGIN1) is involved in the regulation of autophagy by DHA in breast cancer cells and the possible mechanisms involved. DHA upregulated the levels of OSGIN1, LC3-II and SQSTM1/p62. By contrast, DHA dose-dependently decreased the levels of mTOR and p-mTORS2448 expression. Using GFP/RFP-LC3 fluorescence staining, we showed that cells treated with DHA showed a dose-dependent response in autophagic signals. OSGIN1 Overexpression mimicked DHA treatment in that LC3-II and GFP/RFP-LC3 signals as well as the expression of p-AMPKαT172 and p-RaptorS792 were significantly increased, whereas mTOR, p-mTORS2448, and p-ULK1S757 expression were decreased. With knockdown of OSGIN1 expression, these outcomes were reversed. Moreover, OSGIN1 overexpression transiently elevated the accumulation of OSGIN1 and reactive oxygen species (ROS) in the mitochondrial fraction and subsequently increased p-AMPKαT172 and p-RaptorS792 expression. Upon pretreatment with Mito-TEMPO, a scavenger of mitochondrial ROS, these outcomes were reversed. Taken together, these results suggest that DHA can transiently elevate the generation of ROS in mitochondria and promote autophagosome formation through activation of the p-AMPKαT172/p-Raptor S792 and inactivation of the p-mTORS2448/p-ULK1Ser757 signaling pathways, and these effects depend on OSGIN1 protein in MCF-7 cells.

• Authors: Chia-Han Tsai, Chong-Kuei Lii, Tsu-Shing Wang, Kai-Li Liu, Haw-Wen Chen, Chin-Shiu Huang, Chien-Chun Li
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 154 Pg. 112318 (Aug 2021) ISSN: 1873-6351 [Electronic] England
• PMID: 34116103 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• OSGIN1 protein, human
• Reactive Oxygen Species
• Docosahexaenoic Acids
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Adenylate Kinase

Topics

• Adenylate Kinase (metabolism)
• Apoptosis Regulatory Proteins (metabolism)
• Autophagosomes (metabolism)
• Docosahexaenoic Acids (pharmacology)
• Enzyme Activation
• Humans
• MCF-7 Cells
• Mitochondria (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)