RESEARCH ARTICLE

Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα as anti-tumor strategy

  • Jiangmei Li 1 ,
  • Lunfeng Zhang 1,2 ,
  • Zhen Gao 1,2 ,
  • Hua Kang 3 ,
  • Guohua Rong 3 ,
  • Xu Zhang 4 ,
  • Chang Chen , 1,5
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  • 1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China
  • 3. Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
  • 4. Tianjin Research Center of Basic Medical Science, Tianjin Medical University, Tianjin 300070, China
  • 5. 5Beijing Institute for Brain Disorders, Beijing 100069, China

Received date: 26 Feb 2014

Accepted date: 20 Mar 2014

Published date: 26 Jun 2014

Copyright

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Our previous studies indicate that phosphatidylinositol 4-kinase IIα can promote the growth of multi-malignant tumors viaHER-2/PI3K andMAPK pathways.However, the molecular mechanisms of this pathway and its potential for clinical application remain unknown. In this study, we found that PI4KIIα could be an ideal combinatorial target for EGFR treatment via regulating EGFR degradation. Results showed that PI4KIIα knockdown reduced EGFR protein level, and the expression ofPI4KIIα shows a strong correlation with EGFR in human breast cancer tissues (r = 0.77, P<0.01). PI4KIIα knockdown greatly prolonged the effects and decreased the effective dosage ofAG-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 PI4KIIα suppression increased EGFR ligand-independent degradation. Quantitative proteomic analysis by stable isotope labeling with amino acids in cell culture (SILAC) and LC-MS/MS suggested that HSP90mediated the effect of PI4KIIα onEGFR. Furthermore, we found that combined inhibition of PI4KIIα 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 PI4KIIα and EGFR exerts a multiple anti-tumor effect. Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα presents anovel strategy tocombatEGFR-dependent tumors.

Cite this article

Jiangmei Li , Lunfeng Zhang , Zhen Gao , Hua Kang , Guohua Rong , Xu Zhang , Chang Chen . Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα as anti-tumor strategy[J]. Protein & Cell, 2014 , 5(6) : 457 -468 . DOI: 10.1007/s13238-014-0055-y

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