假磷酸化催乳激素持续活化MAPKs抑制前列腺癌侵润

We demonstrated that wild type prolactin promotes cancer cell proliferation, but phosphorylated prolactin promotes cancer cell apoptosis. Via site-directed mutagenesis and DNA cloning we produced a recombinant mimic of phosphorylated PRL（S179D PRL)。The previous studies showed that S179D PRL activated the MAPKs in a sustained way, upregulating p21, leading to prostate cancer cell apoptosis. Our collaborators reported that that S179D PRL in vitro inhibited ovary cell migration. Hence we assume that S179D PRL might inhibit prostate cancer invasion. Our preliminary data showed that S179D PRL downregulated invasion-promoting MMP-2 and MMP-9 to inhibit invasion. Our hypothesis is that S179D PRL activates the MAPKs in a sustained way, downregulating MMP-2 and MMP-9, upregulating invasion-inhibiting TIMP1 and TIMP2, leading to inhibition of invasion of prostate cancer. In this proposal we will use prostate cancer cell lines and in situ xenograft tumor to establish invasion models, to investigate if S179D PRL regulates the invasion-associated proteins and inhibits invasion, and analyze the correlations between these two processes. Through this study, we will find a new way to fight cancer.

野生型催乳激素促进前列腺癌细胞增殖，而磷酸化催乳激素促进凋亡。用定点突变和基因重组技术，我们在大肠杆菌中表达了一种磷酸化催乳激素模拟物（S179D PRL)。研究发现：S179D PRL通过持续活化MAPKs，上调p21，促进前列腺癌细胞凋亡。最近我们的合作者用体外实验证实：S179D PRL能降低卵巢癌细胞迁徙。由此我们设想：S179D PRL可能抑制前列腺癌侵润。本课题前期结果显示：S179D PRL下调侵润促进蛋白MMP-2及MMP-9表达, 抑制前列腺癌细胞侵润。我们的假说是：S179D PRL 持续活化MAPKs，下调MMP-2和MMP-9表达，上调侵润抑制蛋白TIMP1和TIMP2表达，因此抑制前列腺癌侵润。本课题拟建立前列腺癌细胞和裸鼠原位移植瘤侵润模型，在体内体外探索S179D PRL对侵润相关分子的调控和对侵润的抑制，并分析二者的关联。此研究可为治疗肿瘤探索出一条新路。

本研究发现一种假磷酸化的催乳激素模拟物替代物萝卜硫素能够持续地活化ERK1/2，调节几个信号转导通路，抑制肿瘤（不限于前列腺癌）生长和侵润。我们用人前列腺癌、脑胶质母细胞瘤和肺癌细胞模型对这些机理进行了彻底探索，不仅达到了预期效果，而且有相当多惊人的意外发现。萝卜硫素和其衍生物有高效的致凋亡功能，同时抑制侵润。近日我们还发现他们有潜力促进肺癌细胞自噬。尤其，萝卜硫素衍生物能够活化ERK1/2，进而活化几个凋亡和侵润抑制相关信号系统，抑制肿瘤生长。具体地，萝卜硫素衍生物通过活化Caspase 3，降解或下调alpha-tubulin，调节微管的动力学平衡，引起凋亡和抑制侵润。已经有5篇SCI文章（影响因子都在2.5分以上）发表，还有一篇SCI文章刚刚接受，三篇在投，两篇在加工。培养在读和毕业研究生10人，进站博士后3人。这项研究对目前我国化疗药物耐药性强、治疗效果低提供了一个改进的希望，对提高患者的术后生存时间是一个良好的尝试。