Abstract 4948: The cytosolic domain of a disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) proliferation

Abstract

Abstract Emerging evidence has indicated that proteins of a disintergrin and metalloprotease (ADAM) family contribute to cancer progression and metastasis. One member of this family, ADAM15, was reported to over-express in multiple cancers, including gastric, lung, breast, and prostate cancers. It has been shown that the enzymatic activities of its extracellular metalloprotease domain mediate ErbB signaling pathway and promote breast cancer proliferation and migration. Nevertheless, in non-small cell lung cancer (NSCLC), the role of ADAM15 and its correlation to patient prognosis is still not well understood. Moreover, unlike in breast cancer, the enzymatic activities of the ADAM15 extracellular domain appeared to be independent of ErbB signaling and lung cancer proliferation, indicating an alternative mechanism of ADAM15 in promoting lung cancer progression. Here, we demonstrated that ADAM15 was over-expressed in primary NSCLC tissues compared to the adjacent normal tissues. Patients with ADAM15 high-expressing lung tumors had shorter survival times. Furthermore, we examined different isoforms of ADAM15 and discovered that, isoform 6 (i6), which contains the most cytoplasmic Src homology 3 (SH3) binding motifs, was significantly upregulated in primary lung cancer tissues. Comparison of i6 and isoform 1 (i1), which has no cytoplasmic SH3 binding motifs, revealed that the cytoplastmic domain is essential for lung cancer proliferation, as well as aggressiveness in an in vitro lung cancer migration model. We also showed that ADAM15 i6, but not i1, mediated ErbB signaling pathway through physical interaction with growth factor receptor-bound protein 2 (Grb2), and activation of Src homolog 2 domain containing (Shc). Most importantly, overexpression of ADAM15 i6 promoted NSCLC cell growth in a xenograft mouse model while knockdown of i6 resulted in tumor shrinkage. Thus, we identified a novel mechanism of the ADAM15 cytoplasmic domain in NSCLC tumor progression, which will not only shed light on the molecular mechanisms of ADAM proteins, but also facilitate development of novel therapy in NSCLC. Citation Format: Hsin-Han Hou. The cytosolic domain of a disintergrin and metalloprotease (ADAM) 15 promotes non-small cell lung cancer (NSCLC) proliferation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4948. doi:10.1158/1538-7445.AM2015-4948