Abstract 3555: Akt kinase-interacting protein1 as a potential therapeutics target in CREB1 signaling in malignant pleural mesothelioma

Abstract

Abstract Background: Diffuse malignant mesothelioma (DMM) is an aggressive tumor arising from the mesothelial cells of serosal membranes. As conventional treatment regimens are commonly unsuccessful in changing its outcome, novel effective therapeutic strategies based on the molecular mechanisms of disease are needed to improve the prognosis of DMM. Akt kinase-interacting protein1 (Aki1), known as a scaffold protein of PI3K/PDK1/Akt that determines receptor signal selectivity for EGFR, has been suggested as a therapeutic target in lung cancer. The aim of this study was to evaluate Aki1 as a potential therapeutic target for treatment of DMM. Methods: DMM cell lines (211H, H290, H2052, H2373, H2452, Y-meso8A, and Y-meso14) and immortalized human mesothelial cells (Met-5A) were employed for evaluation of effects of treatment with Aki1 or CREB1 siRNAs on cell viability by MTT assay, cell cycle by FACS analysis, cell signaling by WB, and CREB transcriptional activity. The efficacy of Aki1 siRNA against growth of 211H cells was investigated in an orthotropic implantation model using SCID mice. We further examined Aki1 and p-CREB1 expression in DMM tumors from 35 patients utilizing tissue microarray and resection specimens. Results: Cell based assay showed that silencing of Aki1 inhibited cell viability and caused cell arrest of mesothelioma cell lines but not immortalized mesothelial cells (Met-5A). Importantly, we identified that the efficacy of Aki1 is regulated by CREB1 signaling which is involved in cell viability, cell cycle, and transcriptional activity. Application of Aki1 siRNA significantly inhibited growth of 211H cell line within pleural cavity compared with that of control siRNA in an orthotropic implantation model (p = 0.006). Aki1 and phosphorylated CREB1 were frequently expressed in DMM patients (65/68 and 30/35 cases, respectively). Furthermore, the expression of Aki1 correlated with phosphorylation of CREB1 (Spearman rank correlations = 0.521; p = 0.002). Conclusions: Our data suggest that Aki1/CREB axis may regulate the survival signaling, and may therefore be a potent target for DMM patients. Citation Format: Tadaaki Yamada, Joseph M. Amann, Konstantin Shilo, Naoya Fujita, Seiji Yano, David P. Carbone. Akt kinase-interacting protein1 as a potential therapeutics target in CREB1 signaling in malignant pleural mesothelioma. [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 3555. doi:10.1158/1538-7445.AM2015-3555