KCa3.1 Channels Confer Radioresistance to Breast Cancer Cells
KCa3.1 Channels Confer Radioresistance to Breast Cancer Cells
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DOI：
10.3390/cancers11091285
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发表时间：
2019-09-01
期刊：
影响因子：
5.2
通讯作者：
Lukowski, Robert
中科院分区：
文献类型：
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作者：
Mohr, Corinna J.;Gross, Dominic;Lukowski, Robert
据报道，K（Ca）3.1 K+通道有助于乳腺肿瘤细胞的增殖，并可能在微环境中发挥促肿瘤功能。K（Ca）3.1与基于细胞毒性药物或放射疗法的主要抗癌治疗策略的假定相互作用在很大程度上仍未得到探索。我们采用来自乳腺癌易感性MMTV-PyMT小鼠的K（Ca）3.1-完善型和缺乏型乳腺癌细胞、药理学K（Ca）3.1抑制和同基因原位小鼠模型来研究功能性K（Ca）3.1与治疗反应的相关性。MMTV-PyMT细胞的K（Ca）3.1状态在用不同浓度的多西他赛、多柔比星、5-氟尿嘧啶或环磷酰胺处理后不能确定肿瘤细胞增殖。K（Ca）3.1激活电离辐射（IR）在体外乳腺肿瘤细胞，然而，增强辐射抗性，可能通过参与IR刺激的Ca 2+信号和DNA修复途径的通道。一致的是，K（Ca）3.1敲除增加了MMTV-PyMT肿瘤同基因原位移植后接受分次放疗的野生型小鼠的存活时间。结合起来，我们的研究结果表明，K（Ca）3.1赋予耐放射性-但不是化疗的MMTV-PyMT乳腺癌模型。由于K（Ca）3.1是可药物化的，因此K（Ca）3.1靶向伴随放射治疗似乎是一种有前途的乳腺肿瘤放射增敏策略。
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.