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Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIla as anti-tumor strategy

Protein & Cell 2014年第6期5卷 457-468页

作者： Jiangmei Li Lunfeng Zhang Zhen Gao Hua Kang Guohua Rong Xu Zhang Chang Chen National Laboratory of Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China University of Chinese Academy of Sciences Beijing 100049 China Department of General Surgery Xuanwu Hospital Capital Medical University Beijing 100053 China Tianjin Research Center of Basic Medical Science Tianjin Medical University Tianjin 300070 China Beijing Institute for Brain Disorders Beijing 100069 China

Our previous studies indicate that phosphatidylinositol 4-kinase Ila can promote the growth of multi-malignant tumors via HER-2/PI3K and MAPK pathways. However, the molecular mechanisms of this pathway and its potential for clinical application remain unknown. In this study, we found that PI4KIla could be an ideal combinatorial target for EGFR treatment via regulating EGFR degradation. Results showed that PI4KIla knockdown reduced EGFR protein level, and the expression of Pi4KIla shows a strong correlation with EGFR in human breast cancer tissues （r= 0.77, P 〈 0.01）. PI4KIla knockdown greatly prolonged the effects and decreased the effective dosage of AG-1478, a specific inhibitor of EGFR. In addition, it significantly enhanced AG1478-induced inhibition of tumor cell survival and strengthened the effect of the EGFR-targeting anti-cancer drug iressa in xenograft tumor models. Mechanistically, we found that PI4KIla suppression increased EGFR ligand-independent degradation. Quantitative proteomic analysis by stable isotope labeling with amino acids in cell culture （SlLAC） and LC-MS/MS suggested that HsPg0 mediated the effect of PI4KIla on EGFR. Furthermore, we found that combined inhibition of PI4KIla and EGFR suppressed both PI3K/AKT and MAPK/ERK pathways, and resulted in downregulation of multiple oncogenes like PRDX2, FASN, MTA2, ultimately leading to suppression of tumor growth. Therefore, we conclude that combined inhibition of PI4KIla and EGFR exerts a multiple anti-tumor effect. Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIla presents a novel strategy to combat EGFR-dependent tumors.

关键词： phosphatidylinositol 4-kinase Ila (PI4KIla)EGFR dual inhibition enhanced anti-tumor effect breastcancer. iressa

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