PDF(Pubmed)
Abstract：
Translationally controlled tumor protein (TCTP) is expressed in many tissues, particularly in human tumors. It plays a role in malignant transformation, apoptosis prevention, and DNA damage repair. The signaling mechanisms underlying TCTP regulation in cancer are only partially understood. Here, we investigated the role of mTORC1 in regulating TCTP protein levels, thereby modulating chemosensitivity, in human lung cancer cells and an A549 lung cancer xenograft model. The inhibition of mTORC1, but not mTORC2, induced ubiquitin/proteasome-dependent TCTP degradation without a decrease in the mRNA level. PLK1 activity was required for TCTP ubiquitination and degradation and for its phosphorylation at Ser46 upon mTORC1 inhibition. Akt phosphorylation and activation was indispensable for rapamycin-induced TCTP degradation and PLK1 activation, and depended on S6K inhibition, but not mTORC2 activation. Furthermore, the minimal dose of rapamycin required to induce TCTP proteolysis enhanced the efficacy of DNA-damaging drugs, such as cisplatin and doxorubicin, through the induction of apoptotic cell death in vitro and in vivo. This synergistic cytotoxicity of these drugs was induced irrespective of the functional status of p53. These results demonstrate a new mechanism of TCTP regulation in which the mTORC1/S6K pathway inhibits a novel Akt/PLK1 signaling axis and thereby induces TCTP protein stabilization and confers resistance to DNA-damaging agents. The results of this study suggest a new therapeutic strategy for enhancing chemosensitivity in lung cancers regardless of the functional status of p53.
摘要：
翻译控制的肿瘤蛋白（TCTP）在许多组织中表达，特别是在人类肿瘤中。它在恶性转化中起作用，凋亡预防，和DNA损伤修复。在癌症中TCTP调节的信号传导机制仅被部分理解。这里,我们研究了mTORC1在调节TCTP蛋白水平中的作用，从而调节化学敏感性，在人肺癌细胞和A549肺癌异种移植模型中。mTORC1而非mTORC2的抑制诱导泛素/蛋白酶体依赖性TCTP降解而不降低mRNA水平。PLK1活性是TCTP泛素化和降解以及mTORC1抑制后其在Ser46处的磷酸化所必需的。Akt磷酸化和活化对于雷帕霉素诱导的TCTP降解和PLK1活化是必不可少的，依赖于S6K抑制，但不是mTORC2激活。此外，诱导TCTP蛋白水解所需的最小剂量的雷帕霉素增强了DNA损伤药物的功效，如顺铂和阿霉素，通过体外和体内诱导凋亡细胞死亡。无论p53的功能状态如何，都会诱导这些药物的协同细胞毒性。这些结果证明了TCTP调节的新机制,其中mTORC1/S6K途径抑制新的Akt/PLK1信号轴,从而诱导TCTP蛋白稳定并赋予对DNA损伤剂的抗性。这项研究的结果表明，无论p53的功能状态如何，都可以提高肺癌的化学敏感性。
