ABSTRACT
Our previous studies indicate that phosphatidylinositol 4-kinase IIα 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 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 of PI4KIIα 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 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 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 HSP90 mediated the effect of PI4KIIα on EGFR. 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 a novel strategy to combat EGFR-dependent tumors.
Subject(s)
Animals , Female , Humans , Male , Mice , Antineoplastic Agents , Pharmacology , Breast Neoplasms , Metabolism , Pathology , Cell Line, Tumor , Cell Survival , ErbB Receptors , Metabolism , HSP90 Heat-Shock Proteins , Metabolism , MCF-7 Cells , Mice, Inbred BALB C , Mice, Nude , Minor Histocompatibility Antigens , Mitogen-Activated Protein Kinases , Metabolism , Phosphatidylinositol 3-Kinases , Metabolism , Phosphotransferases (Alcohol Group Acceptor) , Genetics , Metabolism , Proto-Oncogene Proteins c-akt , Metabolism , Quinazolines , Pharmacology , Transplantation, Heterologous , Tyrphostins , PharmacologyABSTRACT
Recently many studies have focused on the roles that tumor microenvironment plays in the occurrence and development of tumors,and the therapeutic effects of adjuvant chemotherapy and neoadjuvant chemotherapy.Recent researches show that tumor microenvironment has an obvious impact on the therapeutic effects of neoadjuvant chemotherapy,which mainly includes cancer-associated fibroblasts (CAF),stromal cell derived factor-1 (SDF-1) and collagens.