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Published on: June 20, 2015
Metformin represses bladder cancer progression by inhibiting stem cell repopulation via COX2/PGE2/STAT3 axis
Qiuli Liu1, Wenqiang Yuan1, Dali Tong1
1Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
Abstract:
Cancer stem cells (CSCs) are a sub-population of tumor cells playing essential roles in initiation, differentiation, recurrence, metastasis and development of drug resistance of various cancers, including bladder cancer. Although multiple lines of evidence suggest that metformin is capable of repressing CSC repopulation in different cancers, the effect of metformin on bladder cancer CSCs remains largely unknown. Using the N-methyl-N-nitrosourea (MNU)-induced rat orthotropic bladder cancer model, we demonstrated that metformin is capable of repressing bladder cancer progression from both mild to moderate/severe dysplasia lesions and from carcinoma in situ (CIS) to invasive lesions. Metformin also can arrest bladder cancer cells in G1/S phases, which subsequently leads to apoptosis. And also metformin represses bladder cancer CSC repopulation evidenced by reducing cytokeratin 14 (CK14+) and octamer-binding transcription factor 3/4 (OCT3/4+) cells in both animal and cellular models. More importantly, we found that metformin exerts these anticancer effects by inhibiting COX2, subsequently PGE2 as well as the activation of STAT3. In conclusion, we are the first to systemically demonstrate in both animal and cell models that metformin inhibits bladder cancer progression by inhibiting stem cell repopulation through the COX2/PGE2/STAT3 axis.
Insights
Metformin inhibits bladder cancer progression by reducing cancer stem cells (CSCs). This drug targets the COX2/PGE2/STAT3 pathway, offering a new approach for bladder cancer treatment.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Pharmacology
Background:
- Cancer stem cells (CSCs) drive tumor initiation, metastasis, and drug resistance in various cancers, including bladder cancer.
- Metformin shows potential in repressing CSCs in other cancers, but its effect on bladder cancer CSCs is not well understood.
Purpose of the Study:
- To investigate the effects of metformin on bladder cancer progression and cancer stem cell (CSC) repopulation.
- To elucidate the underlying molecular mechanisms, specifically the role of the COX2/PGE2/STAT3 pathway.
Main Methods:
- Utilized the N-methyl-N-nitrosourea (MNU)-induced rat orthotropic bladder cancer model.
- Assessed metformin's impact on tumor progression, cell cycle arrest, apoptosis, and CSC markers (CK14+, OCT3/4+).
- Investigated the inhibition of COX2, PGE2, and STAT3 activation.
Main Results:
- Metformin repressed bladder cancer progression from dysplasia to invasive lesions.
- Metformin induced G1/S phase arrest and apoptosis in bladder cancer cells.
- Metformin reduced CSC populations (CK14+, OCT3/4+) and inhibited the COX2/PGE2/STAT3 pathway.
Conclusions:
- Metformin effectively inhibits bladder cancer progression and CSC repopulation.
- The anticancer effects of metformin are mediated through the inhibition of the COX2/PGE2/STAT3 signaling axis.
- This study provides the first systemic evidence of metformin's mechanism against bladder cancer via CSC inhibition.
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