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Metformin Suppresses Cancer Stem Cells through AMPK Activation and Inhibition of Protein Prenylation of the Mevalonate Pathway in Colorectal Cancer
Open accessAbstract
Metformin is a well-known AMPK (AMP-activated protein kinase) activator that suppresses cancer stem cells (CSCs) in some cancers. However, the mechanisms of the CSC-suppressing effects of metformin are not yet well understood. In this study, we investigated the CSC-suppressive effect of metformin via the mevalonate (MVA) pathway in colorectal cancer (CRC). Two colorectal cancer cell lines, HT29 and DLD-1 cells, were treated with metformin, mevalonate, or a combination of the two. We measured CSC populations by flow cytometric analysis (CD44+/CD133+) and by tumor spheroid growth. The expression of p-AMPK, mTORC1 (pS6), and key enzymes (HMGCR, FDPS, GGPS1, and SQLE) of the MVA pathway was also analyzed. We investigated the effects of metformin and/or mevalonate in xenograft mice using HT29 cells; immunohistochemical staining for CSC markers and key enzymes of the MVA pathway in tumor xenografts was performed. In both HT29 and DLD-1 cells, the CSC population was significantly decreased following treatment with metformin, AMPK activator (AICAR), HMG-CoA reductase inhibitor (simvastatin), or mTOR inhibitor (rapamycin), and was increased by mevalonate. The CSC-suppressing effect of these drugs was attenuated by mevalonate. The results of tumor spheroid growth matched those of the CSC population experiments. Metformin treatment increased p-AMPK and decreased mTOR (pS6) expression; these effects were reversed by addition of mevalonate. The expression of key MVA pathway enzymes was significantly increased in tumor spheroid culture, and by addition of mevalonate, and decreased upon treatment with metformin, AICAR, or rapamycin. In xenograft experiments, tumor growth and CSC populations were significantly reduced by metformin, and this inhibitory effect of metformin was abrogated by combined treatment with mevalonate. Furthermore, in the MVA pathway, CSC populations were reduced by inhibition of protein prenylation with a farnesyl transferase inhibitor (FTI-277) or a geranylgeranyl transferase inhibitor (GGTI-298), but not by inhibition of cholesterol synthesis with a squalene synthase inhibitor (YM-53601). In conclusion, the CSC-suppressive effect of metformin was associated with AMPK activation and repression of protein prenylation through MVA pathway suppression in colorectal cancer.
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Metformin suppresses the self-renewal capacities of cancer stem cells, evidenced by diminished expression of CSC markers and growth of tumor spheroids through activation of AMPK and inhibition of protein prenylation in the mevalonate pathway.
“metformin also appears to suppress the self-renewal capacities of CSCs, as evidenced by diminished expression of CSC markers (such as CD44 and CD133) and the growth of tumor spheroids through activation of AMP-activated protein kinase (AMPK) and inhibition of protein prenylation in the mevalonate pathway.201”
From Drug repurposing for cancer therapy (2024) · cites this paper as [201]
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Drug repurposing for cancer therapy
Xia, Y., Sun, M., Huang, H., & Jin, W.-L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01808-1 · Cited by 443
Metadata
- Authors
- Seo, Y., Kim, J., Park, S. J., Park, J. J., Cheon, J. H., Kim, W. H., & Kim, T. I.
- Affiliations
- Yonsei University (KR)
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
- Corresponding author
- Kim, Tae Il
- Venue
- Cancers
- Publisher
- MDPI AG
- Published
- 2020-09-08
- Volume
- 12
- Issue
- 9
- Pages
- 2554
- ISSN
- 2072-6694 (ISSN-L)
- PMC
- PMC7563617
- OpenAlex
- W3084238062
- Cited by
- 64
- References
- 1
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 6 · 2023: 14 · 2022: 14 · 2021: 9
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancers (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Research Foundation of Korea (2013R1A1A2010733, 2015R1D1A1A01061002, 2017M3A9G2074773)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- metformin, cancer stem cells, colorectal cancer, AMPK activation, mevalonate pathway, protein prenylation, farnesyltransferase inhibitors, geranylgeranyltransferase inhibitors, mTOR signaling, tumor spheroids, HMG-CoA reductase, cholesterol biosynthesis, drug combination therapy, tumor growth
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