Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent Mechanism
Multiple lines of evidence suggest that metformin, an antidiabetic drug, exerts anti-tumorigenic effects in different types of cancer. Metformin has been reported to affect cancer cells’ metabolism and proliferation mainly through the activation of AMP-activated protein kinase (AMPK). Here, we show...
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MDPI AG
2021-04-01
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| Online Access: | https://www.mdpi.com/2073-4409/10/5/1067 |
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| author | Domenico Conza Paola Mirra Gaetano Calì Luigi Insabato Francesca Fiory Francesco Beguinot Luca Ulianich |
| author_facet | Domenico Conza Paola Mirra Gaetano Calì Luigi Insabato Francesca Fiory Francesco Beguinot Luca Ulianich |
| author_sort | Domenico Conza |
| collection | DOAJ |
| description | Multiple lines of evidence suggest that metformin, an antidiabetic drug, exerts anti-tumorigenic effects in different types of cancer. Metformin has been reported to affect cancer cells’ metabolism and proliferation mainly through the activation of AMP-activated protein kinase (AMPK). Here, we show that metformin inhibits, indeed, endometrial cancer cells’ growth and induces apoptosis. More importantly, we report that metformin affects two important pro-survival pathways, such as the Unfolded Protein Response (UPR), following endoplasmic reticulum stress, and the WNT/β-catenin pathway. GRP78, a key protein in the pro-survival arm of the UPR, was indeed downregulated, while GADD153/CHOP, a transcription factor that mediates the pro-apoptotic response of the UPR, was upregulated at both the mRNA and protein level. Furthermore, metformin dramatically inhibited β-catenin mRNA and protein expression. This was paralleled by a reduction in β-catenin transcriptional activity, since metformin inhibited the activity of a TCF/LEF-luciferase promoter. Intriguingly, compound C, a well-known inhibitor of AMPK, was unable to prevent all these effects, suggesting that metformin might inhibit endometrial cancer cells’ growth and survival through the modulation of specific branches of the UPR and the inhibition of the Wnt/β-catenin pathway in an AMPK-independent manner. Our findings may provide new insights on the mechanisms of action of metformin and refine the use of this drug in the treatment of endometrial cancer. |
| first_indexed | 2024-03-10T11:47:21Z |
| format | Article |
| id | doaj.art-98e0c931fb1d4054bbf9c7894c921590 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T11:47:21Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-98e0c931fb1d4054bbf9c7894c9215902023-11-21T17:58:46ZengMDPI AGCells2073-44092021-04-01105106710.3390/cells10051067Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent MechanismDomenico Conza0Paola Mirra1Gaetano Calì2Luigi Insabato3Francesca Fiory4Francesco Beguinot5Luca Ulianich6Department of Medical and Translational Sciences & Institute of Endocrinology and Experimental Oncology of CNR, University “Federico II”, 80131 Naples, ItalyDepartment of Medical and Translational Sciences & Institute of Endocrinology and Experimental Oncology of CNR, University “Federico II”, 80131 Naples, ItalyInstitute of Endocrinology and Molecular Oncology of CNR, University “Federico II”, 80131 Naples, ItalyDepartment of Advanced Biomedical Sciences, University “Federico II”, 80131 Naples, ItalyDepartment of Medical and Translational Sciences & Institute of Endocrinology and Experimental Oncology of CNR, University “Federico II”, 80131 Naples, ItalyDepartment of Medical and Translational Sciences & Institute of Endocrinology and Experimental Oncology of CNR, University “Federico II”, 80131 Naples, ItalyDepartment of Medical and Translational Sciences & Institute of Endocrinology and Experimental Oncology of CNR, University “Federico II”, 80131 Naples, ItalyMultiple lines of evidence suggest that metformin, an antidiabetic drug, exerts anti-tumorigenic effects in different types of cancer. Metformin has been reported to affect cancer cells’ metabolism and proliferation mainly through the activation of AMP-activated protein kinase (AMPK). Here, we show that metformin inhibits, indeed, endometrial cancer cells’ growth and induces apoptosis. More importantly, we report that metformin affects two important pro-survival pathways, such as the Unfolded Protein Response (UPR), following endoplasmic reticulum stress, and the WNT/β-catenin pathway. GRP78, a key protein in the pro-survival arm of the UPR, was indeed downregulated, while GADD153/CHOP, a transcription factor that mediates the pro-apoptotic response of the UPR, was upregulated at both the mRNA and protein level. Furthermore, metformin dramatically inhibited β-catenin mRNA and protein expression. This was paralleled by a reduction in β-catenin transcriptional activity, since metformin inhibited the activity of a TCF/LEF-luciferase promoter. Intriguingly, compound C, a well-known inhibitor of AMPK, was unable to prevent all these effects, suggesting that metformin might inhibit endometrial cancer cells’ growth and survival through the modulation of specific branches of the UPR and the inhibition of the Wnt/β-catenin pathway in an AMPK-independent manner. Our findings may provide new insights on the mechanisms of action of metformin and refine the use of this drug in the treatment of endometrial cancer.https://www.mdpi.com/2073-4409/10/5/1067metforminendometrial cancerUPRAMPKWnt/β-catenin |
| spellingShingle | Domenico Conza Paola Mirra Gaetano Calì Luigi Insabato Francesca Fiory Francesco Beguinot Luca Ulianich Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent Mechanism Cells metformin endometrial cancer UPR AMPK Wnt/β-catenin |
| title | Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent Mechanism |
| title_full | Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent Mechanism |
| title_fullStr | Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent Mechanism |
| title_full_unstemmed | Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent Mechanism |
| title_short | Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent Mechanism |
| title_sort | metformin dysregulates the unfolded protein response and the wnt β catenin pathway in endometrial cancer cells through an ampk independent mechanism |
| topic | metformin endometrial cancer UPR AMPK Wnt/β-catenin |
| url | https://www.mdpi.com/2073-4409/10/5/1067 |
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