Polarity protein Par3 sensitizes breast cancer to paclitaxel by promoting cell cycle arrest
Polarity protein Par3 sensitizes breast cancer to paclitaxel by promoting cell cycle arrest
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DOI：
10.1007/s10549-021-06490-3
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发表时间：
2021-08
影响因子：
3.8
通讯作者：
Yannan Zhao;Huitong Peng;Limiao Liang;Yi Li;Xichun Hu;Biyun Wang;Ying-Fei Xu;She Chen
中科院分区：
文献类型：
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作者：
Yannan Zhao;Huitong Peng;Limiao Liang;Yi Li;Xichun Hu;Biyun Wang;Ying-Fei Xu;She Chen
目的紫杉醇属于微管蛋白结合剂（TBA），通过稳定微管而显示出抗乳腺癌的良好功效。耐药性限制了其临床应用。本实验旨在探讨极性蛋白Par3在提高紫杉醇疗效中的作用。方法收集45例乳腺癌患者标本，研究Par3表达与紫杉醇疗效的关系。 Kaplan-Meier 方法用于生存分析。在 Par3 过表达或敲低的乳腺癌细胞（SK-BR-3 和 T-47D）中测量细胞活力。进行流式细胞术测定来测量细胞凋亡和细胞周期。进行 BrdU 掺入测定和 Hoechst 33,258 染色分别测量细胞增殖和细胞凋亡。采用免疫荧光法检测微管结构。结果Par3表达与乳腺癌患者紫杉醇的良好反应相关。一致地，Par3 过表达通过促进细胞凋亡和减少细胞增殖，显着使乳腺癌细胞对紫杉醇敏感。在紫杉醇处理后的 Par3 过表达细胞中，我们观察到中期细胞周期停滞加剧。进一步的探索表明，Par3的过表达可以稳定乳腺癌细胞对紫杉醇的反应，并抵抗微管解聚剂诺考达唑引起的微管不稳定。结论Par3促进微管蛋白的聚合形式并稳定微管结构，从而加剧紫杉醇诱导的中期-后期转变延迟，导致乳腺癌细胞增殖抑制和凋亡。 Par3 在使乳腺癌细胞对紫杉醇敏感方面具有潜在作用，这可以为个体治疗和新的治疗靶点提供更精确的评估。
PurposePaclitaxel, belongs to tubulin-binding agents (TBAs), shows a great efficacy against breast cancer via stabilizing microtubules. Drug resistance limits its clinical application. Here we aimed to explore a role of Polarity protein Par3 in improving paclitaxel effectiveness.MethodsBreast cancer specimens from 45 patients were collected to study the relationship between Par3 expression and paclitaxel efficacy. The Kaplan–Meier method was used for survival analysis. Cell viability was measured in breast cancer cells (SK-BR-3 and T-47D) with Par3 over-expression or knockdown. The flow cytometry assays were performed to measure cell apoptosis and cell cycle. BrdU incorporation assay and Hoechst 33,258 staining were performed to measure cell proliferation and cell apoptosis, respectively. Immunofluorescence was used to detect microtubule structures.ResultsPar3 expression was associated with good response of paclitaxel in breast cancer patients. Consistently, Par3 over-expression significantly sensitized breast cancer cells to paclitaxel by promoting cell apoptosis and reducing cell proliferation. In Par3 overexpressing cells upon paclitaxel treatment, we observed intensified cell cycle arrests at metaphase. Further exploration showed that Par3 over-expression stabilized microtubules of breast cancer cells in response to paclitaxel and resists to microtubules instability induced by nocodazole, a microtubule-depolymerizing agent.ConclusionPar3 facilitates polymeric forms of tubulin and stabilizes microtubule structure, which aggravates paclitaxel-induced delay at the metaphase-anaphase transition, leading to proliferation inhibition and apoptosis of breast cancer cells. Par3 has a potential role in sensitizing breast cancer cells to paclitaxel, which may provide a more precise assessment of individual treatment and novel therapeutic targets.