Oncotarget

Research Papers:

IGFBP2 modulates the chemoresistant phenotype in esophageal adenocarcinoma

Amy L. Myers, Lin Lin, Derek J. Nancarrow, Zhuwen Wang, Daysha Ferrer-Torres, Dafydd G. Thomas, Mark B. Orringer, Jules Lin, Rishindra M. Reddy, David G. Beer and Andrew C. Chang _

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Oncotarget. 2015; 6:25897-25916. https://doi.org/10.18632/oncotarget.4532

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Abstract

Amy L. Myers1, Lin Lin1, Derek J. Nancarrow1, Zhuwen Wang1, Daysha Ferrer-Torres1, Dafydd G. Thomas2, Mark B. Orringer1, Jules Lin1, Rishindra M. Reddy1, David G. Beer1, Andrew C. Chang1

1Department of Surgery, University of Michigan, Ann Arbor, MI, USA

2Department of Pathology, University of Michigan, Ann Arbor, MI, USA

Correspondence to:

Andrew C. Chang, e-mail: [email protected]

Keywords: IGFBP2, esophageal cancer, chemotherapy resistance, ERK, AKT

Received: February 22, 2015     Accepted: July 06, 2015     Published: July 17, 2015

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.


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