Epithelial–Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress
Epithelial–mesenchymal transition (EMT) is implicated in tumor metastasis and therapeutic resistance. It remains a challenge to target cancer cells that have undergone EMT. The Snail family of key EMT-inducing transcription factors directly binds to and transcriptionally represses not only epithelia...
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MDPI AG
2022-07-01
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| author | Mingwei Liang Jennifer W. Li Huacheng Luo Sarah Lulu Ozlem Calbay Anitha Shenoy Ming Tan Brian K. Law Shuang Huang Tsan Sam Xiao Hao Chen Lizi Wu Jia Chang Jianrong Lu |
| author_facet | Mingwei Liang Jennifer W. Li Huacheng Luo Sarah Lulu Ozlem Calbay Anitha Shenoy Ming Tan Brian K. Law Shuang Huang Tsan Sam Xiao Hao Chen Lizi Wu Jia Chang Jianrong Lu |
| author_sort | Mingwei Liang |
| collection | DOAJ |
| description | Epithelial–mesenchymal transition (EMT) is implicated in tumor metastasis and therapeutic resistance. It remains a challenge to target cancer cells that have undergone EMT. The Snail family of key EMT-inducing transcription factors directly binds to and transcriptionally represses not only epithelial genes but also a myriad of additional genomic targets that may carry out significant biological functions. Therefore, we reasoned that EMT inherently causes various concomitant phenotypes, some of which may create targetable vulnerabilities for cancer treatment. In the present study, we found that Snail transcription factors bind to the promoters of multiple genes encoding subunits of the AMP-activated protein kinase (AMPK) complex, and expression of AMPK genes was markedly downregulated by EMT. Accordingly, high AMPK expression in tumors correlated with epithelial cell markers and low AMPK expression in tumors was strongly associated with adverse prognosis. AMPK is the principal sensor of cellular energy status. In response to energy stress, AMPK is activated and critically reprograms cellular metabolism to restore energy homeostasis and maintain cell survival. We showed that activation of AMPK by energy stress was severely impaired by EMT. Consequently, EMT cancer cells became hypersensitive to a variety of energy stress conditions and primarily underwent pyroptosis, a regulated form of necrotic cell death. Collectively, the study suggests that EMT impedes the activation of AMPK signaling induced by energy stress and sensitizes cancer cells to pyroptotic cell death under energy stress conditions. Therefore, while EMT promotes malignant progression, it concurrently induces collateral vulnerabilities that may be therapeutically exploited. |
| first_indexed | 2024-03-09T12:05:56Z |
| format | Article |
| id | doaj.art-ac165ca9cf6846ceaca8f7ef30fdd424 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T12:05:56Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-ac165ca9cf6846ceaca8f7ef30fdd4242023-11-30T22:58:40ZengMDPI AGCells2073-44092022-07-011114220810.3390/cells11142208Epithelial–Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy StressMingwei Liang0Jennifer W. Li1Huacheng Luo2Sarah Lulu3Ozlem Calbay4Anitha Shenoy5Ming Tan6Brian K. Law7Shuang Huang8Tsan Sam Xiao9Hao Chen10Lizi Wu11Jia Chang12Jianrong Lu13Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USAGraduate Institute of Biomedical Sciences and Research Center for Cancer Biology, China Medical University, Taichung 406040, TaiwanDepartment of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USADepartment of General Surgery, Second Hospital of Lanzhou University, Lanzhou 730030, ChinaDepartment of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USADepartment of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USAEpithelial–mesenchymal transition (EMT) is implicated in tumor metastasis and therapeutic resistance. It remains a challenge to target cancer cells that have undergone EMT. The Snail family of key EMT-inducing transcription factors directly binds to and transcriptionally represses not only epithelial genes but also a myriad of additional genomic targets that may carry out significant biological functions. Therefore, we reasoned that EMT inherently causes various concomitant phenotypes, some of which may create targetable vulnerabilities for cancer treatment. In the present study, we found that Snail transcription factors bind to the promoters of multiple genes encoding subunits of the AMP-activated protein kinase (AMPK) complex, and expression of AMPK genes was markedly downregulated by EMT. Accordingly, high AMPK expression in tumors correlated with epithelial cell markers and low AMPK expression in tumors was strongly associated with adverse prognosis. AMPK is the principal sensor of cellular energy status. In response to energy stress, AMPK is activated and critically reprograms cellular metabolism to restore energy homeostasis and maintain cell survival. We showed that activation of AMPK by energy stress was severely impaired by EMT. Consequently, EMT cancer cells became hypersensitive to a variety of energy stress conditions and primarily underwent pyroptosis, a regulated form of necrotic cell death. Collectively, the study suggests that EMT impedes the activation of AMPK signaling induced by energy stress and sensitizes cancer cells to pyroptotic cell death under energy stress conditions. Therefore, while EMT promotes malignant progression, it concurrently induces collateral vulnerabilities that may be therapeutically exploited.https://www.mdpi.com/2073-4409/11/14/2208cancerEMTAMPKenergy stressmetforminpyroptosis |
| spellingShingle | Mingwei Liang Jennifer W. Li Huacheng Luo Sarah Lulu Ozlem Calbay Anitha Shenoy Ming Tan Brian K. Law Shuang Huang Tsan Sam Xiao Hao Chen Lizi Wu Jia Chang Jianrong Lu Epithelial–Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress Cells cancer EMT AMPK energy stress metformin pyroptosis |
| title | Epithelial–Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress |
| title_full | Epithelial–Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress |
| title_fullStr | Epithelial–Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress |
| title_full_unstemmed | Epithelial–Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress |
| title_short | Epithelial–Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress |
| title_sort | epithelial mesenchymal transition suppresses ampk and sensitizes cancer cells to pyroptosis under energy stress |
| topic | cancer EMT AMPK energy stress metformin pyroptosis |
| url | https://www.mdpi.com/2073-4409/11/14/2208 |
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