Elimination of cancer stem cells and reactivation of latent HIV-1 via AMPK activation: Common mechanism of action linking inhibition of tumorigenesis and the potential eradication of HIV-1

Cancer stem cells (CSCs) have been reported in various hematopoietic and solid tumors, therefore, are considered to promote cancer progression, metastasis, recurrence and drug resistance. However, regulation of CSCs at the molecular level is not fully understood. microRNAs (miRNAs) have been identified as key regulators of CSCs by modulating their major functions: self-renewal capacity, invasion, migration and proliferation. Various studies suggest that metformin, an anti-diabetic drug, has an anti-tumor activity but its precise mechanism of action has not been understood. The present article was written in accordance to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We systematically reviewed evidence for metformin’s ability to eradicate CSCs through modulating the expression of miRNAs in various solid tumors. PubMed and MEDLINE were searched from January 1990 to January 2020 for in vitro studies. Two authors independently selected and reviewed articles according to predefined eligibility criteria and assessed risk of bias of included studies. Four papers met the inclusion criteria and presented low risk bias. All of the included studies reported a suppression of CSCs’ major function after metformin dosage. Moreover, it was showed that metformin anti-tumor mechanism of action is based on regulation of miRNAs expression. Metformin inhibited cell survival, clonogenicity, wound-healing capacity, sphere formation and promotes chemosensitivity of tumor cells. Due to the small number of publications, aforementioned evidences are limited but may be consider as background for clinical studies.

Download Full-text

Implications of ROS in Cancer Stem Cells Mechanism of Action

10.1007/978-981-15-4501-6_113-1 ◽

2021 ◽

pp. 1-22

Author(s):

Cornelia Amalinei ◽

Raluca Anca Balan ◽

Adriana Grigoras ◽

Ludmila Lozneanu ◽

Elena Roxana Avadanei ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Mechanism Of Action

Download Full-text

Metformin Suppresses Cancer Stem Cells through AMPK Activation and Inhibition of Protein Prenylation of the Mevalonate Pathway in Colorectal Cancer

Cancers ◽

10.3390/cancers12092554 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2554

Author(s):

Yoojeong Seo ◽

Janghyun Kim ◽

Soo Jung Park ◽

Jae Jun Park ◽

Jae Hee Cheon ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Suppressive Effect ◽

Tumor Spheroid ◽

Ampk Activation ◽

Protein Prenylation ◽

Mva Pathway ◽

Key Enzymes ◽

Spheroid Growth

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.

Download Full-text