Role of Insulin-like Growth Factor Binding Protein 2 in Lung Adenocarcinoma: IGF-independent Antiapoptotic Effect Via Caspase-3

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2010 Feb 13

PMID 20150439

Citations 24

Authors

Toshiro Migita

Tadahito Narita

Reimi Asaka

Erika Miyagi

Hiroko Nagano

Kimie Nomura

Masaaki Matsuura

Yukitoshi Satoh

Sakae Okumura

Ken Nakagawa

Hiroyuki Seimiya

Yuichi Ishikawa

Affiliations

Soon will be listed here.

Abstract

Insulin-like growth factor (IGF) signaling plays a pivotal role in cell proliferation and mitogenesis. Secreted IGF-binding proteins (IGFBPs) are important modulators of IGF bioavailability; however, their intracellular functions remain elusive. We sought to assess the antiapoptotic properties of intracellular IGFBP-2 in lung adenocarcinomas. IGFBP-2 overexpression resulted in a decrease in procaspase-3 expression; however, it did not influence the phosphorylation status of either IGF receptor or its downstream targets, including Akt and extracellular signal-regulated kinase. Apoptosis induced by camptothecin was significantly inhibited by IGFBP-2 overexpression in NCI-H522 cells. Conversely, selective knockdown of IGFBP-2 using small-interfering RNA resulted in an increase in procaspase-3 expression and sensitization to camptothecin-induced apoptosis in NCI-H522 cells. LY294002, an inhibitor of phosphatidyl-inositol 3-kinase, caused a decrease in IGFBP-2 levels and enhanced apoptosis in combination with camptothecin. Immunohistochemistry demonstrated that intracellular IGFBP-2 was highly expressed in lung adenocarcinomas compared with normal epithelium. Intracellular IGFBP-2 and procaspase-3 were expressed in a mutually exclusive manner. These findings suggest that intracellular IGFBP-2 regulates caspase-3 expression and contributes to the inhibitory effect on apoptosis independent of IGF. IGFBP-2, therefore, may offer a novel therapeutic target and serve as an antiapoptotic biomarker for lung adenocarcinoma.

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