Profilin 1 potentiates apoptosis induced by staurosporine in cancer cells.
Profilin 1 potentiates apoptosis induced by staurosporine in cancer cells.
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DOI：
10.2174/1566524011313030011
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发表时间：
2013-02
影响因子：
2.5
通讯作者：
W. Yao;X. Cai;Chen Liu;Yi Qin;He Cheng;S. Ji;Wenyan Xu;Chuntao Wu;Tao Chen;Jin Xu;Jiang Long;Z. Fang;Bin Qu;Markus Hoth;Q. Ni;X. Zha;Xianjun Yu
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文献类型：
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作者：
W. Yao;X. Cai;Chen Liu;Yi Qin;He Cheng;S. Ji;Wenyan Xu;Chuntao Wu;Tao Chen;Jin Xu;Jiang Long;Z. Fang;Bin Qu;Markus Hoth;Q. Ni;X. Zha;Xianjun Yu
Profilin 1 （Pfn1）的缺失与肿瘤进展之间的相关性表明Pfn1在人类癌症中是一种肿瘤抑制因子。Pfn1抑制肿瘤的分子机制尚未阐明。在本研究中，我们发现Pfn1过表达通过典型的内在凋亡途径使癌细胞对凋亡敏感。机制上，Pfn1表达的增加介导了p53最常见的肿瘤相关热点突变之一p53R273H的上调，在肿瘤发生过程中发生了反激活缺失，p53R273H在细胞质中的定位增加。进一步的研究表明突变体p53R273H通过转录不依赖的线粒体功能参与Staurosporine （STS）诱导的细胞凋亡。我们观察到(i) p53R273H的胞质定位增加，（ii） Ser15磷酸化活化，（iii）其线粒体定位；Pfn1是这些过程的积极调节因子。我们还发现Pfn1与p53R273H相互作用，从而促进其在药物作用期间在细胞质中发挥转录非依赖性活性。我们的研究结果确定了Pfn1的新功能和机制，表明Pfn1与凋亡药物的联合作用导致细胞凋亡的协同增加。此外，我们发现p53R273H通过不依赖于转激活的胞质活性，在Pfn1致敏的细胞凋亡中发挥重要作用。
The correlation between the loss of Profilin 1 (Pfn1) with tumor progression indicated that Pfn1 is a tumor suppressor in human carcinoma. The molecular mechanisms underlying Pfn1 tumor suppression has yet to be elucidated. In this study, we showed that Pfn1 overexpression sensitizes cancer cells to apoptosis through the typical intrinsic apoptotic pathway. Mechanistically, the increased Pfn1 expression mediated the upregulation of p53R273H, one of the most common tumor-associated hotspot mutations of p53, with transactivation deletion in tumorigenesis and increased localization of p53R273H in cytoplasm. Further studies showed that mutant p53R273H was involved in apoptosis induced by Staurosporine (STS) via transcription-independent mitochondrial functions. We observed (i) the increased cytosolic localization of p53R273H, (ii) the activation of phosphorylation at Ser15, (iii) its mitochondrial localization; Pfn1 acted as a positive regulator of these processes. We also found that Pfn1 interacted with p53R273H and thus facilitated its exertion over the transcription-independent activity in the cytoplasm during drug action. Our results define a new function and mechanism of Pfn1 demonstrating that the combined effect with apoptotic agents led to a synergistic increase in apoptosis. In addition, p53R273H abrogating DNA binding was found to play a major role in the Pfn1- sensitized apoptosis through a transactivation-independent and cytosolic activity.