申请者从事靶向激活腺苷活化蛋白激酶（AMPK）抗结直肠癌的研究。我们从氨基噻唑吡啶杂环化合物的几十种衍生化合物成功筛选了高效小分子AMPK激活剂Hh-009。预实验结果显示：Hh-009激活AMPK信号，并显著抑制结直肠癌细胞增殖，诱导癌细胞自噬。Hh-009还导致EGFR、PDGFR等降解，mTORC1及S6K1-Gli1失活。shRNA敲减AMPKα1则几乎逆转Hh-009抗结直肠癌细胞作用。我们提出Hh-009激活AMPK从而抑制结直肠癌细胞。本课题中，我们将利用分子、细胞生物学及裸鼠荷瘤等方法，体内、外系统观察Hh-009的抗结直肠癌作用，明确激活AMPK在其中的作用；阐明Hh-009激活AMPK的分子机制及下游作用靶点。最后检测AMPKα1在人结直肠癌组织中的表达及活化水平，分析其与各临床指标相关性。旨在明确Hh-009抗结直肠癌作用和分子机制，为结直肠癌治疗学突破进行探索。

Our group has been focusing on targeted-activation of AMP-activated protein kinase (AMPK) signaling to inhibit cancer cells. We have recently developed a novel small molecular AMPK activator, named Hh-009. Our preliminary studies showed that Hh-009 potently activated AMPK signaling in cultured colorectal cancer cells, leading to cancer cell growth inhibition and autophagic cell death. Further, Hh-009 treatment in colorectal cancer cells induced EGFR/PDGFR degradation, whiling causing mTOR complex 1 (mTORC1) and S6K1-Gli1 signaling in-activation. The above effects by Hh-009 were almost reversed by AMPKα1 shRNA knockdown. We propose that Hh-009, a novel AMPK activator, potently inhibits colorectal cancer cells through activating AMPK signaling. We are set to investigate the anti-colorectal cancer activity by Hh-009 in vivo and in vitro, and to study the underlying signaling mechanisms by focusing on AMPK signaling. By using multiple biomedical assays, we will also study how AMPK is activated by Hh-009, and the downstream targets of AMPK activation in colorectal cancer cells. Expression and activation of AMPKα1 in human colorectal cancer tissues will also be tested, and its relationship with tumor staging, patients’ prognosis and other clinical outcomes will be analyzed. This study suggests that activation AMPK signaling might be the key mechanism of Hh-009 in inhibiting colorectal cancer cells. The results of this study will provide theoretical and experimental evidence for using Hh-009 as a novel anti-colorectal cancer agent.