4.6 Article

KCa3.1 Channels Confer Radioresistance to Breast Cancer Cells

期刊

CANCERS
卷 11, 期 9, 页码 -

出版社

MDPI
DOI: 10.3390/cancers11091285

关键词

breast cancer; ionizing radiation; intermediate conductance calcium-activated potassium channel; K(Ca)3.1; SK4; IK; KCNN4; mouse mammary tumor virus polyoma middle T antigen; MMTV-PyMT; TRAM-34

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资金

  1. Deutsche Forschungsgemeinschaft
  2. German Cancer Aid [70112872, 70113144]
  3. ICEPHA Graduate Program Membrane-associated Drug Targets in Personalized Cancer Medicine
  4. Studienstiftung des deutschen Volkes

向作者/读者索取更多资源

K(Ca)3.1 K+ channels reportedly contribute to the proliferation of breast tumor cells and may serve pro-tumor functions in the microenvironment. The putative interaction of K(Ca)3.1 with major anti-cancer treatment strategies, which are based on cytotoxic drugs or radiotherapy, remains largely unexplored. We employed K(Ca)3.1-proficient and -deficient breast cancer cells derived from breast cancer-prone MMTV-PyMT mice, pharmacological K(Ca)3.1 inhibition, and a syngeneic orthotopic mouse model to study the relevance of functional K(Ca)3.1 for therapy response. The K(Ca)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(Ca)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 Ca2+ signals and DNA repair pathways. Consistently, K(Ca)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(Ca)3.1 confers resistance to radio- but not to chemotherapy in the MMTV-PyMT breast cancer model. Since K(Ca)3.1 is druggable, K(Ca)3.1 targeting concomitant to radiotherapy seems to be a promising strategy to radiosensitize breast tumors.

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