Abstract 5270: Activation of B-raf by TCDD effects on chemotherapeutic resistance and potent inhibition of TCDD mediated tumor invasion of papillary thyroid cancer cells by PD98059

Abstract

Abstract The BRAF mutation (V599E) is the most common oncogenic genetic alteration in PTC and, through aberrant activation of the MAPK pathway, can initiate the development and promote the progression of PTC. Constitutive activation of the MAPK pathway through genetic alterations, including RAS and B-type RAF (BRAF) mutations, is common in human cancers and is associated with cell malignant transformation and aggressiveness, implicating that targeted inhibition of the MAPK pathway may potentially be an effective therapy for human cancers. AhR receptor ligands such as TCDD are known to activate mitogen activated protein (MAP) kinases and stress-activated protein kinase/c-Jun NH2-terminal kinase. Here we report that PD98059 successfully inhibits cisplatin-induced apoptosis. And induction of phospho-JNK and phospho-ERK-1/2 were noted when SNU-790 cells were treated with 1 nM TCDD. In in vitro tumor invasion assay, TCDD-induced tumor invasion was reduced by either PD98059 or JNK II inhibitor. PD98059 effectively inhibited TCDD-induced tumor invasion when compared to control. The transcription luciferase reporter system demonstrated that PD98059 effectively reduced AP-1 activity when compared to control. The levels of MMP-2 and MMP-9 mRNA expression were reduced slightly by treatment with PD98059. We conclude a significant association of tumor progression in BRAF mutant PTC with the exposure of TCDD. Our findings suggest that MEK inhibitor (PD98059) may function as a small molecule inhibitor of tumor invasion and may provide novel mechanistic insights into the potential therapy for human ATC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5270.