Luo Guanhong, Wang Weijie, Wu Qiong, Lu Yuanyuan, Su Tao, Gu Nan, Li Kai, Wang Jingbo, Du Rui, Zhao Xiaodi, Li Xiaohua, Fan Rui, Zhang Hongbo, Nie Yongzhan, Zhou Xinmin, Shi Yongquan, Liang Jie, Wang Xin, Fan Daiming
State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China.
Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Oncotarget. 2017 May 11;8(42):71630-71641. doi: 10.18632/oncotarget.17795. eCollection 2017 Sep 22.
Cellular prion protein (PrP), the infective agent of transmissible spongiform encephalopathies, is thought to be related to several cellular physiological and physiopathological processes. We have previously reported that PrP participates in multi-drug-resistance of gastric cancer. As the salient ligand molecule of PrP for participating in internalization and propagation of the scrapie form of prion protein (PrP), 37 kDa laminin receptor precursor protein (37LRP) shared the same gene coding sequence of MGr1-Ag, another protein previously found to be involved in multi-drug-resistance of gastric cancer in our lab. In the present study, we explored whether MGr1-Ag/37LRP contributed to PrP mediated multi-drug-resistance in gastric cancer. Immunohistochemical staining showed similar expression patterns of MGr1-Ag/37LRP and PrP in gastric cancer tissue serial sections. Western blot and immunohistochemistry also demonstrated correlative expression of MGr1-Ag/37LRP and PrP in gastric cancer cell lines. Interaction between MGr1-Ag/37LRP and PrP in gastric cancer cell lines and gastric cancer tissues were verified by immunofluorescence and co-immunoprecipitation. Furthermore, knockdown of MGr1-Ag/37LRP significantly attenuated PrP induced multi-drug-resistance by sensitizing drug-induced apoptosis through inhibition of AKT activation. In conclusion, MGr1-Ag/37LRP may interact with PrP and promote the PrP induced multi-drug-resistance in gastric cancer through PI3K/AKT pathway. The current study elucidates the mechanism of how PrP triggers intracellular signaling cascade resulting in multi-drug-resistance phenotype and provides a novel candidate molecular target against gastric cancer.
细胞朊蛋白（PrP）是传染性海绵状脑病的致病因子，被认为与多种细胞生理和病理生理过程有关。我们之前报道过PrP参与胃癌的多药耐药。作为PrP参与朊病毒蛋白（PrP）瘙痒病形式内化和传播的显著配体分子，37 kDa层粘连蛋白受体前体蛋白（37LRP）与MGr1-Ag具有相同的基因编码序列，MGr1-Ag是我们实验室之前发现的另一种参与胃癌多药耐药的蛋白。在本研究中，我们探讨了MGr1-Ag/37LRP是否促成了PrP介导的胃癌多药耐药。免疫组织化学染色显示，在胃癌组织连续切片中，MGr1-Ag/37LRP和PrP具有相似的表达模式。蛋白质印迹法和免疫组织化学也证明了在胃癌细胞系中MGr1-Ag/37LRP和PrP的相关性表达。通过免疫荧光和免疫共沉淀验证了胃癌细胞系和胃癌组织中MGr1-Ag/37LRP与PrP之间的相互作用。此外，敲低MGr1-Ag/37LRP可通过抑制AKT激活使药物诱导的凋亡敏感化，从而显著减弱PrP诱导的多药耐药。总之，MGr1-Ag/37LRP可能与PrP相互作用，并通过PI3K/AKT途径促进PrP诱导的胃癌多药耐药。本研究阐明了PrP触发细胞内信号级联反应导致多药耐药表型的机制，并为抗胃癌提供了一个新的候选分子靶点。
