title: Inhibition of geranylgeranyl transferase-I decreases cell viability of HTLV-1-transformed cells.
abstract: 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.
authors: Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. edwardsd2@mail.nih.gov
authors: Dustin C
authors: DC
authors: Edwards
authors: Katherine M
authors: KM
authors: McKinnon
authors: Claudio
authors: C
authors: Fenizia
authors: Kyung-Jin
authors: KJ
authors: Jung
authors: John N
authors: JN
authors: Brady
authors: Cynthia A
authors: CA
authors: Pise-Masison
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology*; D002453:Cell Cycle; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002472:Cell Transformation, Viral; D016356:Gene Products, tax / Q000187:drug effects / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000821:virology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D017368:Protein Prenylation / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D001549:Benzamides; C102521:GGTI 298; D016356:Gene Products, tax; D020672:I-kappa B Proteins; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I