Abstract 3444: Exon 4 of osteopontin: A unique target to reduce malignant behavior in non-small cell lung cancer

Abstract

Abstract INTRODUCTION: Osteopontin (OPN) is a ubiquitous protein associated with a wide range of normal and pathologic functions. It is a central regulator of malignant phenotype in non-small cell lung cancer (NSCLC). OPNa, the full length isoform, is disproportionately expressed in NSCLC tumors and cell lines, and increases malignant behavior when over expressed. OPNc, the shortest isoform, does not induce malignant properties when expressed in NSCLC. The only structural difference between OPNa and OPNc is the transcription of exon 4. The hypothesis of this project is that a small interfering peptide to OPN exon 4 will reduce in vitro malignant activity in NSCLC. METHODS: A 16-amino acid peptide which mimics the central sequence in OPN exon 4 and a scrambled sham were constructed and florescent labeled. Three NSCLC cell lines, H358 (low), A549 (moderate), and H460 (high endogenous OPN) were used in binding, proliferation, and invasion assays in presence of exon 4 mimic or sham. Cisplatin sensitivity was performed with peptides in A549. RESULTS: There was florescent evidence for cell surface binding of the exon 4 mimic in all of the NSCLC cell lines without binding of the sham. The exon 4 mimic significantly decreased in vitro invasion and proliferation in the A549 and H460 cell lines, with a lesser effect in H358 with low endogenous OPN. (Table) The exon 4 mimic increased cisplatin sensitivity, decreasing cell viability 2-fold compared to sham and control at cisplatin concentrations 0.1-0.8 uM/ml. CONCLUSIONS: Exon 4 of OPN has not previously been identified as a regulatory region essential for OPN's effect on malignant behavior. We have evidence for an un-described cell surface receptor to this region. A small mimicking peptide to OPN exon 4 significantly decreased in vitro malignant behavior, suggesting interference with important regulatory pathways. This novel binding site could serve as an ideal for target for antibody or small molecule therapies in NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3444. doi:1538-7445.AM2012-3444