RAC1 GTPase promotes the survival of breast cancer cells in response to hyper-fractionated radiation treatment.
RAC1 GTPase promotes the survival of breast cancer cells in response to hyper-fractionated radiation treatment.
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放射治疗是癌症治疗的主要方法，而癌细胞的辐射抵抗仍然是一个重要的临床问题。作为对电离辐射(IR)诱导的DNA损伤的响应，肿瘤细胞可以维持/激活促生存信号通路，导致对细胞凋亡的抵抗，并诱导细胞周期检查点/DNA修复。以往的研究表明，在乳腺癌细胞中，rac1 GTPase过度表达/过度激活，并与不良预后有关。我们实验室的研究表明，在乳腺癌细胞和胰腺癌细胞的IR暴露下，rac1活性是G2/M检查点激活和细胞存活所必需的。在本研究中，我们研究了临床上用于癌症治疗的超分割辐射(HFR)对乳腺癌细胞存活的影响。这份报告的结果表明，与亲本细胞相比，在HFR存活的乳腺癌细胞中，rac1蛋白的表达增加。此外，Rac1的这种增加与ERK1/2和NF-κB信号通路的活性增强以及作为ERK1/2和NF-κB信号通路下游靶点的抗凋亡蛋白Bclxl和Mcl-1的水平增加有关。利用Rac1特异性抑制剂和显性负性突变体N17rac1，我们证明了Rac1抑制降低了乳腺癌细胞中ERK1/2和IκBα的磷酸化，以及Bclxl和Mcl-1蛋白的水平。此外，使用小分子抑制剂或显性阴性的N17rac1抑制rac1可以取消HFR选择的乳腺癌细胞的克隆性存活，并降低完整的PARP水平，这是诱导凋亡的标志。综上所述，本报告中的结果表明，rac1信号对HFR作用下的乳腺癌细胞的生存是必不可少的，并与乳腺癌细胞的辐射抗性有关。这些研究也为探索rac1作为抗辐射乳腺癌细胞的治疗靶点提供了基础。
Radiation therapy is a staple approach for cancer treatment, whereas radioresistance of cancer cells remains a substantial clinical problem. In response to ionizing radiation (IR) induced DNA-damage, cancer cells can sustain/activate pro-survival signaling pathways, leading to apoptotic resistance and induction of cell cycle checkpoint/DNA repair. Previous studies show that Rac1 GTPase is overexpressed/hyperactivated in breast cancer cells and is associated with poor prognosis. Studies from our laboratory reveal that Rac1 activity is necessary for G2/M checkpoint activation and cell survival in response to IR exposure of breast and pancreatic cancer cells. In the present study, we investigated the effect of Rac1 on the survival of breast cancer cells treated with hyper-fractionated radiation (HFR), which is used clinically for cancer treatment. Results in this report indicate that Rac1 protein expression is increased in the breast cancer cells that survived HFR compared to parental cells. Furthermore, this increase of Rac1 is associated with enhanced activities of ERK1/2 and NF-κB signaling pathways and increased levels of anti-apoptotic protein Bcl-xL and Mcl-1, which are downstream targets of ERK1/2 and NF-κB signaling pathways. Using Rac1 specific inhibitor and dominant negative mutant N17Rac1, here we demonstrate that Rac1 inhibition decreases the phosphorylation of ERK1/2 and IκBα, as well as the levels of Bcl-xL and Mcl-1 protein in the HFR-selected breast cancer cells. Moreover, inhibition of Rac1 using either small molecule inhibitor or dominant negative N17Rac1 abrogates clonogenic survival of HFR-selected breast cancer cells and decreases the level of intact PARP, which is indicative of apoptosis induction. Collectively, results in this report suggest that Rac1 signaling is essential for the survival of breast cancer cells subjected to HFR and implicate Rac1 in radioresistance of breast cancer cells. These studies also provide the basis to explore Rac1 as a therapeutic target for radioresistant breast cancer cells.
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