The Role of PHLPP in Colon Cancer

结直肠癌是美国癌症相关死亡的第二大原因。约 预计2019年将有145，000例新病例和51，000例死亡;这一死亡率主要是由于 对现有治疗方案的反应不佳。更好地理解导致 为了提高癌症患者的总体存活率，需要癌症进展和化学抗性。 我的实验室一直致力于阐明一个新的蛋白磷酸酶家族PHLPP的作用 (PH结构域富含亮氨酸重复序列的蛋白磷酸酶），抑制结肠癌的发生和发展。我们 在理解PHLPP作为肿瘤抑制因子的功能重要性方面取得了实质性进展， 以及PHLPP调控的分子机制。本研究的总体目标是进一步 发展PHLPP介导的细胞应激反应调节机制的理解， 细胞存活和肿瘤发生。在最近令人兴奋的发现中，我们证明了化疗诱导的ER 应激促进PHLPP降解，而PHLPP缺失通过上调 eIF 2 α/ATF 4介导的信号传导。此外，我们发现下调PHLPP可以促进线粒体的 通过调节Drp 1磷酸化来分裂。总的来说，推动这项拟议研究的中心假设是 PHLPP在CRC中充当重要的应激传感器，其中细胞应激信号触发PHLPP降解 促进细胞存活和肿瘤发生。提出了以下具体目标：1）界定 PHLPP介导的eIF 2 α/ATF 4信号调节的分子机制我们将确定是否 PHLPP的下调使结肠癌细胞由于自噬而对化疗药物产生抗性 激活; 2）确定PHLPP介导的线粒体动力学调节的功能重要性。 我们将通过以下方法来检验PHLPP在调节线粒体动力学中起重要作用的假设： 增强Drp 1活性以科普促炎应激信号;以及3）确定 线粒体动力学与PHLPP-损失协同促进体内肿瘤发生。我们将使用Drp 1 和PHLPP基因敲除小鼠，以确定PHLPP和Drp 1在调节结肠功能方面的相互作用 癌症体内肿瘤发生。我们提出的研究集中在一个新的假设上，即PHLPP的损失在 在协调细胞应激信号下游的多种促生存反应中发挥关键作用， 肿瘤发生我们的研究将填补一个重要的知识空白，改变线粒体动力学如何有助于 与结肠癌的发生和发展有关。最终，通过提供对PHLPP的机械见解- 压力反应的依赖性调节，我们的研究结果将有助于确定新的治疗方案，并更好地预测 基于癌症患者PHLPP状态的化疗药物的有效性。

Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately 145,000 new cases and 51,000 deaths are predicted for the year 2019; and this mortality is predominantly due to poor responses to available treatment options. A better understanding of the molecular events leading to cancer progression and chemoresistance is needed in order to improve the overall survival of cancer patients. My lab has been intensively focused on elucidating the role of a novel family of protein phosphatases, PHLPP (PH domain Leucine-rich-repeats Protein Phosphatase), in inhibiting colon cancer initiation and progression. We have made substantial progress in understanding the functional importance of PHLPP as a tumor suppressor as well as the molecular mechanism underlying PHLPP regulation. The overall objective of this study is to further develop a mechanistic understanding of PHLPP-mediated regulation of cellular stress response in supporting cell survival and tumorigenesis. In exciting recent findings, we demonstrated that chemotherapy-induced ER stress promotes PHLPP degradation and PHLPP-loss provides a survival advantage by upregulating eIF2α/ATF4-mediated signaling. In addition, we found that downregulation of PHLPP promotes mitochondrial fission by regulating Drp1 phosphorylation. Collectively, the central hypothesis driving this proposed study is that PHLPP serves an essential stress sensor in CRC, in which cellular stress signals trigger PHLPP degradation to promote cell survival and tumorigenesis. The following specific aims are proposed: 1) to delineate the molecular mechanism underlying PHLPP-mediated regulation of eIF2α/ATF4 signaling. We will determine if downregulation of PHLPP renders colon cancer cells resistant to chemotherapy drugs as a result of autophagy activation; 2) to determine the functional importance of PHLPP-mediated regulation of mitochondrial dynamics. We will test the hypothesis that PHLPP plays an important role in regulating mitochondrial dynamics by enhancing Drp1 activity in order to cope with proinflammatory stress signals; and 3) to define the role of mitochondrial dynamics in cooperating with PHLPP-loss to promote tumorigenesis in vivo. We will utilize Drp1 and PHLPP knockout mice to determine the function interaction between PHLPP and Drp1 on regulating colon cancer tumorigenesis in vivo. Our proposed study centers on a novel hypothesis that that PHLPP-loss plays a pivotal role in orchestrating multiple pro-survival responses downstream of cellular stress signals to promote tumorigenesis. Our study will fill an important knowledge gap on how altered mitochondrial dynamics contributes to tumor initiation and progression in colon cancer. Ultimately, by providing mechanistic insights into PHLPP- dependent regulation of stress response, our findings will help identify new treatment options and better predict the effectiveness of chemotherapy agents based on PHLPP status in cancer patients.