Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy
The calcium-permeable cation channel TRPM8 (transient receptor potential melastatin 8) is a member of the TRP superfamily of cation channels that is upregulated in various types of cancer with high levels of autophagy, including prostate, pancreatic, breast, lung, and colon cancers. Autophagy is clo...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-12-01
|
| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2020.573127/full |
| _version_ | 1818431502934867968 |
|---|---|
| author | Yuan Huang Shi Li Zhenhua Jia Weiwei Zhao Cefan Zhou Rui Zhang Declan William Ali Marek Michalak Xing-Zhen Chen Jingfeng Tang |
| author_facet | Yuan Huang Shi Li Zhenhua Jia Weiwei Zhao Cefan Zhou Rui Zhang Declan William Ali Marek Michalak Xing-Zhen Chen Jingfeng Tang |
| author_sort | Yuan Huang |
| collection | DOAJ |
| description | The calcium-permeable cation channel TRPM8 (transient receptor potential melastatin 8) is a member of the TRP superfamily of cation channels that is upregulated in various types of cancer with high levels of autophagy, including prostate, pancreatic, breast, lung, and colon cancers. Autophagy is closely regulated by AMP-activated protein kinase (AMPK) and plays an important role in tumor growth by generating nutrients through degradation of intracellular structures. Additionally, AMPK activity is regulated by intracellular Ca2+ concentration. Considering that TRPM8 is a non-selective Ca2+-permeable cation channel and plays a key role in calcium homoeostasis, we hypothesized that TRPM8 may control AMPK activity thus modulating cellular autophagy to regulate the proliferation and migration of breast cancer cells. In this study, overexpression of TRPM8 enhanced the level of basal autophagy, whereas TRPM8 knockdown reduced the level of basal autophagy in several types of mammalian cancer cells. Moreover, the activity of the TRPM8 channel modulated the level of basal autophagy. The mechanism of regulation of autophagy by TRPM8 involves autophagy-associated signaling pathways for activation of AMPK and ULK1 and phagophore formation. Impaired AMPK abolished TRPM8-dependent regulation of autophagy. TRPM8 interacts with AMPK in a protein complex, and cytoplasmic C-terminus of TRPM8 mediates the TRPM8–AMPK interaction. Finally, basal autophagy mediates the regulatory effects of TRPM8 on the proliferation and migration of breast cancer cells. Thus, this study identifies TRPM8 as a novel regulator of basal autophagy in cancer cells acting by interacting with AMPK, which in turn activates AMPK to activate ULK1 in a coordinated cascade of TRPM8-mediated breast cancer progression. |
| first_indexed | 2024-12-14T15:50:20Z |
| format | Article |
| id | doaj.art-db99a86c78b940cd8e78ea60913ed425 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-14T15:50:20Z |
| publishDate | 2020-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-db99a86c78b940cd8e78ea60913ed4252022-12-21T22:55:24ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-12-011010.3389/fonc.2020.573127573127Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal AutophagyYuan Huang0Shi Li1Zhenhua Jia2Weiwei Zhao3Cefan Zhou4Rui Zhang5Declan William Ali6Marek Michalak7Xing-Zhen Chen8Jingfeng Tang9National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, ChinaNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, ChinaNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, ChinaNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, ChinaNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, ChinaNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, ChinaMembrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry of Alberta, Edmonton, AB, CanadaDepartment of Biochemistry, University of Alberta, Edmonton, AB, CanadaMembrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry of Alberta, Edmonton, AB, CanadaNational “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan, ChinaThe calcium-permeable cation channel TRPM8 (transient receptor potential melastatin 8) is a member of the TRP superfamily of cation channels that is upregulated in various types of cancer with high levels of autophagy, including prostate, pancreatic, breast, lung, and colon cancers. Autophagy is closely regulated by AMP-activated protein kinase (AMPK) and plays an important role in tumor growth by generating nutrients through degradation of intracellular structures. Additionally, AMPK activity is regulated by intracellular Ca2+ concentration. Considering that TRPM8 is a non-selective Ca2+-permeable cation channel and plays a key role in calcium homoeostasis, we hypothesized that TRPM8 may control AMPK activity thus modulating cellular autophagy to regulate the proliferation and migration of breast cancer cells. In this study, overexpression of TRPM8 enhanced the level of basal autophagy, whereas TRPM8 knockdown reduced the level of basal autophagy in several types of mammalian cancer cells. Moreover, the activity of the TRPM8 channel modulated the level of basal autophagy. The mechanism of regulation of autophagy by TRPM8 involves autophagy-associated signaling pathways for activation of AMPK and ULK1 and phagophore formation. Impaired AMPK abolished TRPM8-dependent regulation of autophagy. TRPM8 interacts with AMPK in a protein complex, and cytoplasmic C-terminus of TRPM8 mediates the TRPM8–AMPK interaction. Finally, basal autophagy mediates the regulatory effects of TRPM8 on the proliferation and migration of breast cancer cells. Thus, this study identifies TRPM8 as a novel regulator of basal autophagy in cancer cells acting by interacting with AMPK, which in turn activates AMPK to activate ULK1 in a coordinated cascade of TRPM8-mediated breast cancer progression.https://www.frontiersin.org/articles/10.3389/fonc.2020.573127/fullautophagyLC3Btransient receptor potential melastatin 8 (TRPM8)AMP-activated protein kinase(AMPK)cancer |
| spellingShingle | Yuan Huang Shi Li Zhenhua Jia Weiwei Zhao Cefan Zhou Rui Zhang Declan William Ali Marek Michalak Xing-Zhen Chen Jingfeng Tang Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy Frontiers in Oncology autophagy LC3B transient receptor potential melastatin 8 (TRPM8) AMP-activated protein kinase(AMPK) cancer |
| title | Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy |
| title_full | Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy |
| title_fullStr | Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy |
| title_full_unstemmed | Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy |
| title_short | Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy |
| title_sort | transient receptor potential melastatin 8 trpm8 channel regulates proliferation and migration of breast cancer cells by activating the ampk ulk1 pathway to enhance basal autophagy |
| topic | autophagy LC3B transient receptor potential melastatin 8 (TRPM8) AMP-activated protein kinase(AMPK) cancer |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2020.573127/full |
| work_keys_str_mv | AT yuanhuang transientreceptorpotentialmelastatin8trpm8channelregulatesproliferationandmigrationofbreastcancercellsbyactivatingtheampkulk1pathwaytoenhancebasalautophagy AT shili transientreceptorpotentialmelastatin8trpm8channelregulatesproliferationandmigrationofbreastcancercellsbyactivatingtheampkulk1pathwaytoenhancebasalautophagy AT zhenhuajia transientreceptorpotentialmelastatin8trpm8channelregulatesproliferationandmigrationofbreastcancercellsbyactivatingtheampkulk1pathwaytoenhancebasalautophagy AT weiweizhao transientreceptorpotentialmelastatin8trpm8channelregulatesproliferationandmigrationofbreastcancercellsbyactivatingtheampkulk1pathwaytoenhancebasalautophagy AT cefanzhou transientreceptorpotentialmelastatin8trpm8channelregulatesproliferationandmigrationofbreastcancercellsbyactivatingtheampkulk1pathwaytoenhancebasalautophagy AT ruizhang transientreceptorpotentialmelastatin8trpm8channelregulatesproliferationandmigrationofbreastcancercellsbyactivatingtheampkulk1pathwaytoenhancebasalautophagy AT declanwilliamali transientreceptorpotentialmelastatin8trpm8channelregulatesproliferationandmigrationofbreastcancercellsbyactivatingtheampkulk1pathwaytoenhancebasalautophagy AT marekmichalak transientreceptorpotentialmelastatin8trpm8channelregulatesproliferationandmigrationofbreastcancercellsbyactivatingtheampkulk1pathwaytoenhancebasalautophagy AT xingzhenchen transientreceptorpotentialmelastatin8trpm8channelregulatesproliferationandmigrationofbreastcancercellsbyactivatingtheampkulk1pathwaytoenhancebasalautophagy AT jingfengtang transientreceptorpotentialmelastatin8trpm8channelregulatesproliferationandmigrationofbreastcancercellsbyactivatingtheampkulk1pathwaytoenhancebasalautophagy |