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Published on: March 1, 2020
Inhibitory effects of metformin at low concentration on epithelial-mesenchymal transition of CD44(+)CD117(+) ovarian
Rongrong Zhang1, Ping Zhang2, Hong Wang3
1Department of Gynecology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China. rrzhangcn@126.com.
Background:
Although metformin, a first-line drug for treating diabetes, may play an important role in inhibition of epithelial ovarian cancer cell growth and cancer stem cells (CSCs), metformin at low dose showed less effect on the proliferation of ovarian cancer cells. In this study, we evaluated the effect of metformin at low dose on ovarian CSCs in order to understand the molecular mechanisms underlying.
Methods:
The inhibitory effects of metformin at los dose on proliferation and population of ovarian cancer cells including SKOV3 and A2780 were assessed by cell proliferation assay and flow cytometry. Quantitative real-time PCR assay on expression of Bcl-2, Survivin and Bax was performed to determine the effect of metformin at low dose on epithelial-mesenchymal transition (EMT) of cancer cells and CSCs. Tumor sphere formation assay was also performed to evaluate the effect of metformin on spheres forming ability of CSCs. The therapeutic efficacy and the anti-CSC effects of metformin at low dose were investigated by using both SKOV3 cells and primary tumor xenografts. In addition, the CSC frequency and EMT in tumor xenograft models were also assessed by flow cytometry and quantitative real-time PCR.
Results:
Metformin at low dose did not affect the proliferation of ovarian cancer cells. However, it inhibited population of CD44(+)CD117(+) selectively, neither CD133(+) nor ALDH(+) cells. It suppressed expression of snail2, twist and vimentin significantly in cancer cells and CD44(+)CD117(+) CSCs in vitro. Low dose of metformin reduced survivin expression in CSCs. Low concentrations of metformin inhibited the secondary and the tertiary tumor sphere formation, decreased SKOV3 and primary ovarian tumor xenograft growth, enhanced the anticancer effect of cisplatin, and lowered the proportion of CD44(+)CD117(+) CSCs in the xenograft tissue. Metformin was also associated with a reduction of snail2, twist, and vimentin in CD44(+)CD117(+) ovarian CSCs in vivo.
Conclusions:
Our results implicate that metformin at low dose inhibits selectively CD44(+)CD117(+) ovarian CSCs through inhibition of EMT and potentiates the effect of cisplatin.
Insights
Low-dose metformin selectively targets ovarian cancer stem cells (CSCs) by inhibiting epithelial-mesenchymal transition (EMT), enhancing cisplatin therapy. This study reveals metformin
Area of Science:
- Oncology
- Pharmacology
- Cancer Stem Cell Biology
Background:
- Metformin, a first-line diabetes drug, shows potential in inhibiting ovarian cancer cell growth and cancer stem cells (CSCs).
- Low-dose metformin exhibits limited efficacy on ovarian cancer cell proliferation, necessitating further investigation into its effects on CSCs.
Purpose of the Study:
- To evaluate the effect of low-dose metformin on ovarian CSCs.
- To elucidate the molecular mechanisms underlying the action of low-dose metformin on ovarian CSCs, particularly focusing on epithelial-mesenchymal transition (EMT).
Main Methods:
- Assessed metformin's effects on ovarian cancer cell proliferation and population using cell proliferation assays and flow cytometry.
- Quantified gene expression of Bcl-2, Survivin, and Bax via real-time PCR to evaluate EMT.
- Utilized tumor sphere formation assays and in vivo xenograft models (SKOV3 and primary tumors) to assess anti-CSC effects and therapeutic efficacy.
Main Results:
- Low-dose metformin did not inhibit overall ovarian cancer cell proliferation but selectively reduced the CD44(+)CD117(+) CSC population.
- Metformin suppressed key EMT markers (snail2, twist, vimentin) and survivin expression in CSCs both in vitro and in vivo.
- In vivo, low-dose metformin inhibited tumor growth, reduced CSC proportion, and enhanced cisplatin's anticancer effects.
Conclusions:
- Low-dose metformin selectively targets CD44(+)CD117(+) ovarian CSCs by inhibiting EMT.
- Metformin at low concentrations potentiates the therapeutic efficacy of cisplatin in ovarian cancer treatment.
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