小分子肽RPL41对转录因子ATF4的调控机制及其在卵巢癌治疗中的应用

Ovarian cancer is one of the major threats to women's health and life, which has the highest mortality rate of all gynecologic malignancy. Two major challenges in the treatment of ovarian cancer include metastasis and drug resistance. Transcription factor ATF4 promotes tumor aggression and drug resistance via signaling a protective response to cell stress. Previous studies showed that ATF4 upregulates VEGF-A and uPA by binding to their promoters, VEGF-A and uPA play important roles in angiogenesis and tumor metastasis. ATF4 is over-expressed in many tumors including ovarian cancer, and is considered a candidate therapeutic target. In vitro studies showed that the down regulation of ATF4 inhibited tumor growth in mice and also sensitized tumors to various chemotherapy; however, Anti-ATF4 strategy in cancer therapy has never been tested in vivo due to the lack of systematically usable anti-ATF4 agents. Ribosomal protein RPL41 is a tumor suppressor initially identified in our laboratory. RPL41 is a small peptide of 25 amino acids, which can be chemically synthesized; a synthetic RPL41 is water-soluble, self-cell penetrating, and therefore have potential as a systemic drug. Our preliminary studies showed that RPL41 is capable of inducing ATF4 phosphorylation and rapid degradation in proteasome. To the best of our knowledge, RPL41 is the only known systematic-usable anti-ATF4 agent. We are proposing to further determine the critical kinase for RPL41-induced ATF4 phosphorylation and degradation; we will also study whether RPL41 can be used to treat ovarian cancer using in vitro cell models and in vivo animal models.

卵巢癌是严重威胁妇女生命的恶性肿瘤 ,其死亡率位居妇科恶性肿瘤首位，转移和耐药是卵巢癌难治的重要原因。转录因子ATF4是肿瘤生长转移和耐药的一个重要信号通路。ATF4能够与VEGF-A、uPA启动子结合，增强其转录活性来上调二者表达，在卵巢癌的生长转移中发挥着重要的作用。利用基因调控方法下调ATF4表达能够抑制肿瘤细胞的生长侵袭或者增加肿瘤对其它化疗药物敏感性。然而，目前还没有有效的抗ATF4药物。RPL41是我们最新发现的一个肿瘤抑制基因。前期研究发现RPL41是一种可以自由穿透细胞膜的小分子肽，能够诱导细胞内ATF4磷酸化，移位至蛋白酶体中迅速降解，是目前唯一一种抗ATF4的药物。本项目是在前期重要发现基础上，通过系列体内外实验深入研究RPL41诱导ATF4磷酸化降解的内在机制，以及RPL41对卵巢癌的抑制作用和分子机制，为卵巢癌的治疗提供新靶点。

卵巢癌是严重威胁妇女生命的恶性肿瘤 ,其死亡率位居妇科恶性肿瘤首位，转移和耐药是卵巢癌难治的重要原因。转录因子ATF4是肿瘤生长转移和耐药的一个重要信号通路。ATF4能够与VEGF-A、uPA启动子结合，增强其转录活性来上调二者表达，在卵巢癌的生长转移中发挥着重要的作用。利用基因调控方法下调ATF4表达能够抑制肿瘤细胞的生长侵袭或者增加肿瘤对其它化疗药物敏感性。然而，目前还没有有效的抗ATF4药物。RPL41是我们最新发现的一个肿瘤抑制基因，我们研究发现RPL41是一种可以自由穿透细胞膜的小分子肽，能够诱导细胞内ATF4磷酸化，移位至蛋白酶体中迅速降解，是目前唯一一种抗ATF4的药物；DAPK是RPL41降解ATF4的关键酶，DAPK激酶是通过磷酸化ATF4S219位点来降解ATF4；RPL41通过降解ATF4下调VEGF-A、uPA等的表达抑制卵巢癌细胞生长转移，为卵巢癌的治疗提供新靶点。

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