PAK4抑制自噬在胃癌中的作用及机制研究

p21-activated kinases(PAKs) are a family of conserved serine/threonine protein kinase which were recognized as one of the key signaling pathway regulators in tumor cells. And the research about PAK4, the representative member among PAKs, is still on the early stage. Since the role of autophagy in tumorigenesis, development and drug resistance is not yet clear, the research about it has attracted widespread attention. Recently, we found that PAK4 could inhibit autophagy in gastric cancer cells for the first time. So the aim of our project is to further confirm the inhibition of autophagy by PAK4, find the binding protein or its phosphorylation substrates during the regulating process, identify the binding regions or phosphorylating sites, and also explore the mechanism underlying the process which PAK4 involved in the regulation of autophagy. Then, we will try to analyze the relationship between the process which PAK4 regulates autophagy and the degree of tumor differentiation, TNM staging and tumor prognosis. To sum up, this project will help us clarify the effect and mechanism of PAK4 involved in autophagy, reveal the influence of the gastic cancer progression and prognosis which resulted by the inbibition of PAK4, and provide new sights to identify novel therapeutic targets for gastric cancer.

P21活化激酶（P21-activated kinases，PAKs）为一类保守的丝/苏氨酸蛋白激酶，被认为是肿瘤细胞内信号网络的关键调节因子之一，其成员PAK4的研究正处于起步阶段。自噬在肿瘤发生发展及耐药过程中所起的作用尚不明确，是目前肿瘤研究中的热点。实验中我们首次发现PAK4能够抑制胃癌细胞发生自噬。本课题旨在进一步验证PAK4抑制自噬的作用；明确PAK4调控自噬过程中的相互作用蛋白及磷酸化底物，确定PAK4与自噬相关蛋白的结合区域及对底物的磷酸化位点，研究PAK4参与自噬调控的分子机制；结合胃癌样本及患者资料检验PAK4调控自噬的过程与肿瘤分化程度、TNM分期及预后之间的关系。通过上述研究，阐明PAK4抑制自噬的作用及具体分子机制，揭示PAK4抑制自噬对于胃癌进展程度及患者预后的影响，为寻找胃癌治疗靶点提供新的理论依据。

自噬在肿瘤发生发展及耐药过程中所起的作用尚不明确，是目前肿瘤研究中的热点。P21活化激酶（P21-activated kinases，PAKs）为一类进化上保守的丝/苏氨酸蛋白激酶，被认为是肿瘤细胞内信号网络的关键调节因子之一，其成员PAK4的研究正处于起步阶段。实验中我们首次发现PAK4能够抑制胃癌细胞发生自噬。本课题进一步从多角度验证了PAK4抑制自噬的作用；明确了PAK4调控自噬过程中的相互作用蛋白及磷酸化底物，确定PAK4与自噬相关蛋白的结合区域及对底物的磷酸化作用，解析PAK4参与自噬调控的分子机制。同时，在实验中发现我们自主研发的PAK4小分子抑制剂LCH-7749944能够促进胃癌细胞发生自噬并探讨了可能的作用机制。通过上述研究，阐明PAK4抑制胃癌细胞发生自噬的作用及具体分子机制，为寻找胃癌治疗靶点提供新的理论依据。