K<sub>Ca</sub>3.1 Channels Confer Radioresistance to Breast Cancer Cells
K<sub>Ca</sub>3.1 K<sup>+</sup> channels reportedly contribute to the proliferation of breast tumor cells and may serve pro-tumor functions in the microenvironment. The putative interaction of K<sub>Ca</sub>3.1 with major anti-cancer treatment strategies, which ar...
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| Format: | Article |
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MDPI AG
2019-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/9/1285 |
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| author | Corinna J. Mohr Dominic Gross Efe C. Sezgin Friederike A. Steudel Peter Ruth Stephan M. Huber Robert Lukowski |
| author_facet | Corinna J. Mohr Dominic Gross Efe C. Sezgin Friederike A. Steudel Peter Ruth Stephan M. Huber Robert Lukowski |
| author_sort | Corinna J. Mohr |
| collection | DOAJ |
| description | K<sub>Ca</sub>3.1 K<sup>+</sup> channels reportedly contribute to the proliferation of breast tumor cells and may serve pro-tumor functions in the microenvironment. The putative interaction of K<sub>Ca</sub>3.1 with major anti-cancer treatment strategies, which are based on cytotoxic drugs or radiotherapy, remains largely unexplored. We employed K<sub>Ca</sub>3.1-proficient and -deficient breast cancer cells derived from breast cancer-prone MMTV-PyMT mice, pharmacological K<sub>Ca</sub>3.1 inhibition, and a syngeneic orthotopic mouse model to study the relevance of functional K<sub>Ca</sub>3.1 for therapy response. The K<sub>Ca</sub>3.1 status of MMTV-PyMT cells did not determine tumor cell proliferation after treatment with different concentrations of docetaxel, doxorubicin, 5-fluorouracil, or cyclophosphamide. K<sub>Ca</sub>3.1 activation by ionizing radiation (IR) in breast tumor cells in vitro, however, enhanced radioresistance, probably via an involvement of the channel in IR-stimulated Ca<sup>2+</sup> signals and DNA repair pathways. Consistently, K<sub>Ca</sub>3.1 knockout increased survival time of wildtype mice upon syngeneic orthotopic transplantation of MMTV-PyMT tumors followed by fractionated radiotherapy. Combined, our results imply that K<sub>Ca</sub>3.1 confers resistance to radio- but not to chemotherapy in the MMTV-PyMT breast cancer model. Since K<sub>Ca</sub>3.1 is druggable, K<sub>Ca</sub>3.1 targeting concomitant to radiotherapy seems to be a promising strategy to radiosensitize breast tumors. |
| first_indexed | 2024-03-12T07:11:16Z |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T07:11:16Z |
| publishDate | 2019-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-86973dff5c0b4b02ba89aa718ab8fc9e2023-09-02T23:04:32ZengMDPI AGCancers2072-66942019-09-01119128510.3390/cancers11091285cancers11091285K<sub>Ca</sub>3.1 Channels Confer Radioresistance to Breast Cancer CellsCorinna J. Mohr0Dominic Gross1Efe C. Sezgin2Friederike A. Steudel3Peter Ruth4Stephan M. Huber5Robert Lukowski6Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Radiation Oncology, University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Radiation Oncology, University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, 72076 Tuebingen, GermanyK<sub>Ca</sub>3.1 K<sup>+</sup> channels reportedly contribute to the proliferation of breast tumor cells and may serve pro-tumor functions in the microenvironment. The putative interaction of K<sub>Ca</sub>3.1 with major anti-cancer treatment strategies, which are based on cytotoxic drugs or radiotherapy, remains largely unexplored. We employed K<sub>Ca</sub>3.1-proficient and -deficient breast cancer cells derived from breast cancer-prone MMTV-PyMT mice, pharmacological K<sub>Ca</sub>3.1 inhibition, and a syngeneic orthotopic mouse model to study the relevance of functional K<sub>Ca</sub>3.1 for therapy response. The K<sub>Ca</sub>3.1 status of MMTV-PyMT cells did not determine tumor cell proliferation after treatment with different concentrations of docetaxel, doxorubicin, 5-fluorouracil, or cyclophosphamide. K<sub>Ca</sub>3.1 activation by ionizing radiation (IR) in breast tumor cells in vitro, however, enhanced radioresistance, probably via an involvement of the channel in IR-stimulated Ca<sup>2+</sup> signals and DNA repair pathways. Consistently, K<sub>Ca</sub>3.1 knockout increased survival time of wildtype mice upon syngeneic orthotopic transplantation of MMTV-PyMT tumors followed by fractionated radiotherapy. Combined, our results imply that K<sub>Ca</sub>3.1 confers resistance to radio- but not to chemotherapy in the MMTV-PyMT breast cancer model. Since K<sub>Ca</sub>3.1 is druggable, K<sub>Ca</sub>3.1 targeting concomitant to radiotherapy seems to be a promising strategy to radiosensitize breast tumors.https://www.mdpi.com/2072-6694/11/9/1285breast cancerionizing radiationintermediate conductance calcium-activated potassium channelK<sub>Ca</sub>3.1SK4IKKCNN4mouse mammary tumor virus polyoma middle T antigenMMTV-PyMTTRAM-34 |
| spellingShingle | Corinna J. Mohr Dominic Gross Efe C. Sezgin Friederike A. Steudel Peter Ruth Stephan M. Huber Robert Lukowski K<sub>Ca</sub>3.1 Channels Confer Radioresistance to Breast Cancer Cells Cancers breast cancer ionizing radiation intermediate conductance calcium-activated potassium channel K<sub>Ca</sub>3.1 SK4 IK KCNN4 mouse mammary tumor virus polyoma middle T antigen MMTV-PyMT TRAM-34 |
| title | K<sub>Ca</sub>3.1 Channels Confer Radioresistance to Breast Cancer Cells |
| title_full | K<sub>Ca</sub>3.1 Channels Confer Radioresistance to Breast Cancer Cells |
| title_fullStr | K<sub>Ca</sub>3.1 Channels Confer Radioresistance to Breast Cancer Cells |
| title_full_unstemmed | K<sub>Ca</sub>3.1 Channels Confer Radioresistance to Breast Cancer Cells |
| title_short | K<sub>Ca</sub>3.1 Channels Confer Radioresistance to Breast Cancer Cells |
| title_sort | k sub ca sub 3 1 channels confer radioresistance to breast cancer cells |
| topic | breast cancer ionizing radiation intermediate conductance calcium-activated potassium channel K<sub>Ca</sub>3.1 SK4 IK KCNN4 mouse mammary tumor virus polyoma middle T antigen MMTV-PyMT TRAM-34 |
| url | https://www.mdpi.com/2072-6694/11/9/1285 |
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