IGFBP2 modulates the chemoresistant phenotype in esophageal adenocarcinoma.
Oncotarget, 2015/9/22;6(28):25897-916.
Myers AL[1], Lin L[1], Nancarrow DJ[1], Wang Z[1], Ferrer-Torres D[1], Thomas DG[2], Orringer MB[1], Lin J[1], Reddy RM[1], Beer DG[1], Chang AC[1]
Affiliations
PMID: 26317790DOI: 10.18632/oncotarget.4532
Abstract
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.
Keywords: AKT; ERK; IGFBP2; chemotherapy resistance; esophageal cancer
MeSH terms
Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cisplatin; Culture Media, Serum-Free; Drug Resistance, Neoplasm; Esophageal Neoplasms; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor I; MAP Kinase Signaling System; Male; Middle Aged; RNA Interference; Reverse Transcriptase Polymerase Chain Reaction; Survival Analysis
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