ggti-298 and Cell-Transformation--Viral

Human T-cell leukemia virus type-1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL), an aggressive and highly chemoresistant malignancy. Rho family GTPases regulate multiple signaling pathways in tumorigenesis: cytoskeletal organization, transcription, cell cycle progression, and cell proliferation. Geranylgeranylation of Rho family GTPases is essential for cell membrane localization and activation of these proteins. It is currently unknown whether HTLV-1-transformed cells are preferentially sensitive to geranylgeranylation inhibitors, such as GGTI-298. In this report, we demonstrate that GGTI-298 decreased cell viability and induced G(2)/M phase accumulation of HTLV-1-transformed cells, independent of p53 reactivation. HTLV-1-LTR transcriptional activity was inhibited and Tax protein levels decreased following treatment with GGTI-298. Furthermore, GGTI-298 decreased activation of NF-κB, a downstream target of Rho family GTPases. These studies suggest that protein geranylgeranylation contributes to dysregulation of cell survival pathways in HTLV-1-transformed cells.

Topics: Alkyl and Aryl Transferases; Benzamides; Cell Cycle; Cell Line, Transformed; Cell Survival; Cell Transformation, Viral; Gene Products, tax; Human T-lymphotropic virus 1; Humans; I-kappa B Proteins; Leukemia-Lymphoma, Adult T-Cell; NF-kappa B; Phosphorylation; Protein Prenylation; Protein Transport; Signal Transduction; Tumor Suppressor Protein p53