Abstract B27: SERPINE1 expression is required for HDACi-induced proliferative arrest in ras-transformed epithelial cells

Abstract

Abstract Malignant transformation of mammalian cells with ras family oncogenes results in dramatic changes in cellular architecture and growth traits. The generation of flat revertants of v-K-ras-transformed epithelial cells by exposure to the histone deacetylase inhibitor sodium butyrate (NaB) was found to be dependent on transcriptional activation of the SERPINE1 gene (encoding the type-1 inhibitor of urokinase and tissue-type plasminogen activators; PAI-1). NaB-initiated SERPINE1 expression preceded induced cell spreading and G1 arrest. To assess the relevance of SERPINE1 induction to proliferative blockade in this cell system more critically, several complementary approaches were used. The addition of a stable, long half-life, recombinant SERPINE1 mutant to SERPINE1-deficient v-K-ras-/c-Ha-ras-transformants or to SERPINE1 functionally null, NaB-resistant, 4HH cells (engineered by antisense knockdown of SERPINE1 mRNA transcripts) resulted in marked cytostasis in the absence of NaB. Transfection of ras-transformed cells with the Rc/CMVSERPINE1 expression vector or infection with an adenoviral SERPINE1 construct, moreover, significantly elevated constitutive SERPINE1 synthesis (10- to 20-fold) with a concomitant reduction in proliferative rate. These data suggest that high-level SERPINE1 expression suppresses growth of chronic ras-oncogene transformed cells and is likely a major cytostatic effector of NaB exposure. Supported by NIH grant GM057242. Note: This abstract was not presented at the conference. Citation Format: Paul J. Higgins. SERPINE1 expression is required for HDACi-induced proliferative arrest in ras-transformed epithelial cells. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B27. doi: 10.1158/1557-3125.RASONC14-B27