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IGFBP2 modulates the chemoresistant phenotype in esophageal adenocarcinoma

, : IGFBP2 modulates the chemoresistant phenotype in esophageal adenocarcinoma. Oncotarget 6(28): 25897-25916

Esophageal adenocarcinoma (EAC) patients commonly present with advanced stage disease and demonstrate resistance to therapy, with response rates below 40%. Understanding the molecular mechanisms of resistance is crucial for improvement of clinical outcomes. IGFBP2 is a member of the IGFBP family of proteins that has been reported to modulate both IGF and integrin signaling and is a mediator of cell growth, invasion and resistance in other tumor types. In this study, high IGFBP2 expression was observed in a subset of primary EACs and was found to be significantly higher in patients with shorter disease-free intervals as well as in treatment-resistant EACs as compared to chemonaive EACs. Modulation of IGFBP2 expression in EAC cell lines promoted cell proliferation, migration and invasion, implicating a role in the metastatic potential of these cells. Additionally, knockdown of IGFBP2 sensitized EAC cells to cisplatin in a serum-dependent manner. Further in vitro exploration into this chemosensitization implicated both the AKT and ERK pathways. Silencing of IGFBP2 enhanced IGF1-induced immediate activation of AKT and reduced cisplatin-induced ERK activation. Addition of MEK1/2 (selumetinib or trametinib) or AKT (AKT Inhibitor VIII) inhibitors enhanced siIGFBP2-induced sensitization of EAC cells to cisplatin. These results suggest that targeted inhibition of IGFBP2 alone or together with either the MAPK or PI3K/AKT signaling pathway in IGFBP2-overexpressing EAC tumors may be an effective approach for sensitizing resistant EACs to standard neoadjuvant chemotherapy.


PMID: 26317790

DOI: 10.18632/oncotarget.4532

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