IKCa channels control breast cancer metabolism including AMPK-driven autophagy
Abstract Ca2+-activated K+ channels of intermediate conductance (IK) are frequently overexpressed in breast cancer (BC) cells, while IK channel depletion reduces BC cell proliferation and tumorigenesis. This raises the question, of whether and mechanistically how IK activity interferes with the meta...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05329-z |
| _version_ | 1811198101624455168 |
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| author | Dominic Gross Helmut Bischof Selina Maier Katharina Sporbeck Andreas L. Birkenfeld Roland Malli Peter Ruth Tassula Proikas-Cezanne Robert Lukowski |
| author_facet | Dominic Gross Helmut Bischof Selina Maier Katharina Sporbeck Andreas L. Birkenfeld Roland Malli Peter Ruth Tassula Proikas-Cezanne Robert Lukowski |
| author_sort | Dominic Gross |
| collection | DOAJ |
| description | Abstract Ca2+-activated K+ channels of intermediate conductance (IK) are frequently overexpressed in breast cancer (BC) cells, while IK channel depletion reduces BC cell proliferation and tumorigenesis. This raises the question, of whether and mechanistically how IK activity interferes with the metabolic activity and energy consumption rates, which are fundamental for rapidly growing cells. Using BC cells obtained from MMTV-PyMT tumor-bearing mice, we show that both, glycolysis and mitochondrial ATP-production are reduced in cells derived from IK-deficient breast tumors. Loss of IK altered the sub-/cellular K+- and Ca2+- homeostasis and mitochondrial membrane potential, ultimately resulting in reduced ATP-production and metabolic activity. Consequently, we find that BC cells lacking IK upregulate AMP-activated protein kinase activity to induce autophagy compensating the glycolytic and mitochondrial energy shortage. Our results emphasize that IK by modulating cellular Ca2+- and K+-dynamics contributes to the remodeling of metabolic pathways in cancer. Thus, targeting IK channel might disturb the metabolic activity of BC cells and reduce malignancy. |
| first_indexed | 2024-04-12T01:26:10Z |
| format | Article |
| id | doaj.art-36dbb1c4c62044baa46ffea7e80eab74 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T01:26:10Z |
| publishDate | 2022-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-36dbb1c4c62044baa46ffea7e80eab742022-12-22T03:53:39ZengNature Publishing GroupCell Death and Disease2041-48892022-10-01131011410.1038/s41419-022-05329-zIKCa channels control breast cancer metabolism including AMPK-driven autophagyDominic Gross0Helmut Bischof1Selina Maier2Katharina Sporbeck3Andreas L. Birkenfeld4Roland Malli5Peter Ruth6Tassula Proikas-Cezanne7Robert Lukowski8Department of Pharmacology, Toxicology and Clinical Pharmacology, Institute of Pharmacy, University of TübingenDepartment of Pharmacology, Toxicology and Clinical Pharmacology, Institute of Pharmacy, University of TübingenDepartment of Pharmacology, Toxicology and Clinical Pharmacology, Institute of Pharmacy, University of TübingenDepartment of Molecular Biology, Interfaculty Institute of Cell Biology, University of TübingenInstitute of Diabetes Research and Metabolic Diseases (IDM), the Helmholtz CenterGottfried Schatz Research Center for Cell Signalling, Metabolism and Aging, Division of Molecular Biology and Biochemistry, Medical University of GrazDepartment of Pharmacology, Toxicology and Clinical Pharmacology, Institute of Pharmacy, University of TübingenDepartment of Molecular Biology, Interfaculty Institute of Cell Biology, University of TübingenDepartment of Pharmacology, Toxicology and Clinical Pharmacology, Institute of Pharmacy, University of TübingenAbstract Ca2+-activated K+ channels of intermediate conductance (IK) are frequently overexpressed in breast cancer (BC) cells, while IK channel depletion reduces BC cell proliferation and tumorigenesis. This raises the question, of whether and mechanistically how IK activity interferes with the metabolic activity and energy consumption rates, which are fundamental for rapidly growing cells. Using BC cells obtained from MMTV-PyMT tumor-bearing mice, we show that both, glycolysis and mitochondrial ATP-production are reduced in cells derived from IK-deficient breast tumors. Loss of IK altered the sub-/cellular K+- and Ca2+- homeostasis and mitochondrial membrane potential, ultimately resulting in reduced ATP-production and metabolic activity. Consequently, we find that BC cells lacking IK upregulate AMP-activated protein kinase activity to induce autophagy compensating the glycolytic and mitochondrial energy shortage. Our results emphasize that IK by modulating cellular Ca2+- and K+-dynamics contributes to the remodeling of metabolic pathways in cancer. Thus, targeting IK channel might disturb the metabolic activity of BC cells and reduce malignancy.https://doi.org/10.1038/s41419-022-05329-z |
| spellingShingle | Dominic Gross Helmut Bischof Selina Maier Katharina Sporbeck Andreas L. Birkenfeld Roland Malli Peter Ruth Tassula Proikas-Cezanne Robert Lukowski IKCa channels control breast cancer metabolism including AMPK-driven autophagy Cell Death and Disease |
| title | IKCa channels control breast cancer metabolism including AMPK-driven autophagy |
| title_full | IKCa channels control breast cancer metabolism including AMPK-driven autophagy |
| title_fullStr | IKCa channels control breast cancer metabolism including AMPK-driven autophagy |
| title_full_unstemmed | IKCa channels control breast cancer metabolism including AMPK-driven autophagy |
| title_short | IKCa channels control breast cancer metabolism including AMPK-driven autophagy |
| title_sort | ikca channels control breast cancer metabolism including ampk driven autophagy |
| url | https://doi.org/10.1038/s41419-022-05329-z |
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