Abstract 4602: Blocking of p14/ARF and DX2 binding by novel small chemical can improve the chemo-sensitivity of small cell lung cancer and non-small cell lung carcinoma

Abstract

In recent, it has been reported that alternative splicing variant of AIMP2, AIMP2/DX2 (DX2), is frequently expressed in human lung cancer and is related with p53-mediated tumor suppression pathway. Here we show that DX2 can promote tumor progression and increase incidence, cooperatively with oncogenic K-Ras in transgenic mouse model. Moreover, it can induce small cell lung carcinoma (SCLC) as well as contribute to progression of non-small cell lung carcinoma (NSCLC). In fact, DX2 expression is elevated in human small cell lung cancer cell lines. Based on the cellular localization and responsibility of si-DX2, we revealed that DX2 is an inhibitor of p14/ARF. Elimination of DX2 can induce p14/ARF expression and DX2 Transgenic (Tg) mouse cells show the low expression of p19/ARF. Since DX2, but not its original product AIMP2, is selectively interacted with p14/ARF, we screened the specific binding inhibitor and obtained the single compound (SLC36) from about 9000 chemicals. This chemical can block the interaction of p14/ARF-DX2 and also AIMP2-DX2, but not the binding of p14/ARF-p53 or AIMP2-p53. In addition, it can induce p14/ARF expression and cell death in human lung cancer cell lines including SCLC cell lines. In our in vivo study, treatment of SLC36, combined with low dosage of adriamycin (1 mg/kg) can suppress the cancer incidence as well as progression in K-RasLA2 and K-Ras/DX2 double Tg model. These results indicate that DX2 can contribute to lung cancer progression and development, including SCLC, through inhibition of p14/ARF, and blocking of DX2-p14/ARF binding would be useful therapeutic strategy of human lung cancers including SCLC as well as NSCLC. Citation Format: Ah Young Oh, Youn-Sang Jung, Su-Jin Lee, Jung Hyun Jo, Ho Young Chun, Bum-Joon Park. Blocking of p14/ARF and DX2 binding by novel small chemical can improve the chemo-sensitivity of small cell lung cancer and non-small cell lung carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4602. doi:10.1158/1538-7445.AM2014-4602