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Article

Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis

1
Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
2
University of Chinese Academy of Sciences, Beijing 100864, China
*
Authors to whom correspondence should be addressed.
Present address: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
Academic Editors: Hung-Chi Cheng, Chun-Li Su and Ming-Fen Lee
Life 2022, 12(1), 42; https://doi.org/10.3390/life12010042
Received: 30 October 2021 / Revised: 14 December 2021 / Accepted: 15 December 2021 / Published: 28 December 2021
(This article belongs to the Special Issue Tumor Progression, Microenvironments, and Therapeutics)
Metastasis arises owing to tumor cells’ capacity to evade pro-apoptotic signals. Anoikis—the apoptosis of detached cells (from the extracellular matrix (ECM)) is often circumvented by metastatic cells as a result of biochemical and molecular transformations. These facilitate cells’ ability to survive, invade and reattach to secondary sites. Here, we identified deregulated glucose metabolism, oxidative phosphorylation, and proteasome in anchorage-independent cells compared to adherent cells. Metformin an anti-diabetic drug that reduces blood glucose (also known to inhibit mitochondrial Complex I), and proteasome inhibitors were employed to target these changes. Metformin or proteasome inhibitors alone increased misfolded protein accumulation, sensitized tumor cells to anoikis, and impaired pulmonary metastasis in the B16F10 melanoma model. Mechanistically, metformin reduced cellular ATP production, activated AMPK to foster pro-apoptotic unfolded protein response (UPR) through enhanced expression of CHOP in ECM detached cells. Furthermore, AMPK inhibition reduced misfolded protein accumulation, thus highlight relevance of AMPK activation in facilitating metformin-induced stress and UPR cell death. Our findings provide insights into the molecular biology of anoikis resistance and identified metformin and proteasome inhibitors as potential therapeutic options for tumor metastasis. View Full-Text
Keywords: anoikis; metastasis; oxidative phosphorylation; proteasome; AMPK anoikis; metastasis; oxidative phosphorylation; proteasome; AMPK
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MDPI and ACS Style

Adeshakin, F.O.; Adeshakin, A.O.; Liu, Z.; Cheng, J.; Zhang, P.; Yan, D.; Zhang, G.; Wan, X. Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis. Life 2022, 12, 42. https://doi.org/10.3390/life12010042

AMA Style

Adeshakin FO, Adeshakin AO, Liu Z, Cheng J, Zhang P, Yan D, Zhang G, Wan X. Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis. Life. 2022; 12(1):42. https://doi.org/10.3390/life12010042

Chicago/Turabian Style

Adeshakin, Funmilayo O., Adeleye O. Adeshakin, Zhao Liu, Jian Cheng, Pengchao Zhang, Dehong Yan, Guizhong Zhang, and Xiaochun Wan. 2022. "Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis" Life 12, no. 1: 42. https://doi.org/10.3390/life12010042

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