Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits
Funmilayo O Adeshakin1,2, Adeleye O Adeshakin1,2, Zhao Liu1
1Guangdong 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.
Abstract:
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.
Insights
Metformin and proteasome inhibitors target cancer cells that resist anoikis, a form of apoptosis. These drugs induce stress, leading to tumor cell death and reduced metastasis.
Area of Science:
- Molecular Biology
- Cancer Research
- Metabolism
Background:
- Metastasis involves tumor cells evading apoptosis, particularly anoikis (apoptosis of detached cells).
- Metastatic cells develop resistance to anoikis through molecular and biochemical changes.
- Anchorage-independent cancer cells exhibit altered glucose metabolism, oxidative phosphorylation, and proteasome activity.
Purpose of the Study:
- To investigate the metabolic vulnerabilities of anchorage-independent cancer cells.
- To evaluate the therapeutic potential of targeting deregulated metabolism in metastatic cells.
- To explore the role of metformin and proteasome inhibitors in overcoming anoikis resistance.
Main Methods:
- Comparison of metabolic profiles between adherent and anchorage-independent cells.
- Treatment of B16F10 melanoma cells with metformin or proteasome inhibitors.
- Assessment of misfolded protein accumulation, anoikis sensitization, and pulmonary metastasis.
- Investigation of the underlying molecular mechanisms involving ATP production, AMPK activation, and unfolded protein response (UPR).
Main Results:
- Anchorage-independent cells showed deregulated glucose metabolism, oxidative phosphorylation, and proteasome function.
- Metformin and proteasome inhibitors increased misfolded protein accumulation and sensitized cells to anoikis.
- These agents significantly impaired pulmonary metastasis in a melanoma model.
- Metformin reduced ATP production and activated AMPK, promoting UPR and CHOP expression in detached cells.
- AMPK inhibition counteracted metformin's effects, confirming its role in stress induction and cell death.
Conclusions:
- Metformin and proteasome inhibitors represent promising therapeutic strategies against tumor metastasis.
- Targeting metabolic alterations and inducing endoplasmic reticulum stress can overcome anoikis resistance.
- The findings provide crucial insights into the molecular mechanisms of anoikis resistance and potential treatments.
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