Chronic administration of metformin exerts cytostatic and cytotoxic effects via the PP2A-GSK3β-MCL-1 pathway by inhibiting the tmCLIC1 membrane protein in glioblastoma-initiating cells
Abstract
BACKGROUND: One of the main challenges in cancer treatment is addressing the metabolic reprogramming of tumor cells, which require more energy and biomolecules than healthy cells. Cancer cells alter their metabolism by switching between glycolysis and oxidative phosphorylation (OXPHOS). These processes depend on transmembrane proteins that respond to the extracellular environment. Our research identified the transmembrane form of Chloride Intracellular Channel 1 (tmCLIC1) as a marker of malignancy and a potential therapeutic target. tmCLIC1 levels are increased in several solid tumors, supporting cancer growth and progression, whereas they are mostly absent in healthy cells. We confirmed that tmCLIC1 is the specific target of the antidiabetic drug metformin, an OXPHOS inhibitor in cancer cells.
METHODS: tmCLIC1 is the primary target of metformin in glioblastoma-initiating cells, as shown by single-channel patch-clamp recordings and NMR experiments. Various patient-derived glioblastoma cells with different genetic backgrounds were used to demonstrate that CLIC1 CRISPR-Cas9 knockout and/or its point mutation at arginine 29 removes metformin's antitumor effects. Functional assays were used to assess the effects on proliferation, mitochondrial metabolism, and tumor growth in vitro and in vivo, using zebrafish and murine xenograft models.
RESULTS: Metformin inhibits the function of tmCLIC1 through direct and specific binding involving arginine 29 in the tmCLIC1 sequence.…
Read the paper
Related studies
- Metformin as an adjuvant in breast cancer treatment
- Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
- Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice
- Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines
- Protein Interaction Network for Identifying Vascular Response of Metformin (Oral Antidiabetic)
- Preventing Long COVID With Metformin
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.