PARK2 promotes mitochondrial pathway of apoptosis and antimicrotubule drugs chemosensitivity via degradation of phospho-BCL-2
PARK2 promotes mitochondrial pathway of apoptosis and antimicrotubule drugs chemosensitivity via degradation of phospho-BCL-2
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PARK2 通过降解磷酸-BCL-2 促进线粒体凋亡途径和抗微管药物化学敏感性
DOI：
10.7150/thno.47044
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Yin, Dong
中科院分区：
文献类型：
--
作者：
Chen, Hengxing;Li, Yun;Yin, Dong
基本原理：新辅助化疗已成为局部晚期乳腺癌的标准治疗。抗微管药物和DNA损伤药物是新辅助化疗最常用的药物。然而，我们无法预测哪种化疗药物对个体患者有益。PARK 2作为乳腺癌的肿瘤抑制因子已有报道。而PARK 2在化疗反应中的作用尚不清楚。在这项研究中，我们探讨PARK 2对乳腺癌化疗敏感性的影响。方法：应用免疫组化方法检测不同新辅助化疗方案的乳腺癌组织中PARK 2的表达。数据与无病生存期（DFS）、总生存期和病理完全缓解（pCR）相关。PARK 2的功能作用通过一系列体外和体内实验得到证实。包括质谱、免疫共沉淀、亚细胞分离、荧光显微镜、体内泛素化分析和荧光素酶分析。结果如下：PARK 2高表达预示着对含抗微管药物方案的反应更好，与更高的病理完全缓解率（pCR）相关。相反，PARK 2表达不能预测对DNA损伤药物方案的反应。在抗微管药物治疗后，PARK 2的水平由于STAT 3介导的PARK 2的转录抑制的抑制而上调。此外，PARK 2的过表达特异性地使细胞对抗微管药物更敏感，但对DNA损伤药物不敏感。PARK 2的缺失增强了抗微管药物的耐药性。在机制上，PARK 2在暴露于抗微管药物后显著激活凋亡的线粒体途径。这是通过下调抗凋亡蛋白磷酸化BCL-2而发生的。抗微管药物可以特异性地诱导BCL-2磷酸化，而DNA损伤药物则不能。值得注意的是，PARK 2与磷酸化BCL-2（Ser 70）相互作用，并以E3连接酶依赖的方式促进BCL-2的泛素化。因此，PARK 2在体外和体内均显着增强了抗微管药物的化学敏感性，而功能丧失的PARK 2突变体则没有。结论：我们的研究结果解释了为什么PARK 2选择性地赋予抗微管药物的化学敏感性，而不是DNA损伤药物。此外，我们确定PARK 2作为一种新的介质的抗微管药物的敏感性，它可以预测乳腺癌患者的反应，抗微管药物的方案。
Rationale: Neoadjuvant chemotherapy has become the standard treatment of locally advanced breast cancer. Antimicrotubule drugs and DNA-damaging drugs are the most popular medicines used for neoadjuvant chemotherapy. However, we are unable to predict which chemotherapeutic drug will benefit to an individual patient. PARK2 as a tumor suppressor in breast cancer has been reported. While the role of PARK2 in chemotherapy response remains unknown. In this study, we explore the impact of PARK2 on chemosensitivity in breast cancer. Methods: PARK2 expression in breast cancer patients with different neoadjuvant chemotherapeutic regimens was studied using immunohistochemistry. Data was correlated to disease-free survival (DFS), overall survival and pathologic complete response (pCR). The functional roles of PARK2 were demonstrated by a series of in vitro and in vivo experiments. Including mass spectrometry, Co-immunoprecipitation, isolation of subcellular fractionation, fluorescence microscopy, in vivo ubiquitination assay and luciferase analyses. Results: Highly expressed PARK2 predicted better response to antimicrotubule drugs-containing regimen associated with higher rate of pathologic complete response (pCR). In contrast, PARK2 expression did not predict response to the DNA-damaging drugs regimen. Following antimicrotubule drugs treatment, levels of PARK2 was upregulated due to the repression of STAT3-mediated transcriptional inhibition of PARK2. Moreover, overexpression of PARK2 specifically rendered cells more sensitive to antimicrotubule drugs, but not to DNA-damaging drugs. Depletion of PARK2 enhanced resistance to antimicrotubule drugs. Mechanistically, PARK2 markedly activated the mitochondrial pathway of apoptosis after exposure to antimicrotubule drugs. This occurred through downregulating the antiapoptotic protein, phospho-BCL-2. BCL-2 phosphorylation can be specifically induced by antimicrotubule drugs, whereas DNA-damaging drugs do not. Notably, PARK2 interacted with phospho-BCL-2 (Ser70) and promoted ubiquitination of BCL-2 in an E3 ligase-dependent manner. Hence, PARK2 significantly enhanced the chemosensitivity of antimicrotubule drugs both in vitro and in vivo, while loss-of-function PARK2 mutants did not. Conclusions: Our findings explained why PARK2 selectively confers chemosensitivity to antimicrotubule drugs, but not to DNA-damaging drugs. In addition, we identified PARK2 as a novel mediator of antimicrotubule drugs sensitivity, which can predict response of breast cancer patients to antimicrotubule drugs-containing regime.