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Viruses 2011, 3(10), 1815-1835; doi:10.3390/v3101815
Article

Inhibition of Geranylgeranyl Transferase-I Decreases Cell Viability of HTLV-1-Transformed Cells

1
, 2
, 2
, 1
, 1,† and 1,*
1 Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA 2 Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Deceased.
* Author to whom correspondence should be addressed.
Received: 13 September 2011 / Accepted: 26 September 2011 / Published: 10 October 2011
(This article belongs to the Special Issue Recent Developments in HTLV Research)
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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 G2/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.
Keywords: human T-cell leukemia virus type-1; HTLV-1; Tax; long terminal repeat; LTR; geranylgeranyltransferase; GGTI-298; small GTPase; NF-κB; p53; cell cycle human T-cell leukemia virus type-1; HTLV-1; Tax; long terminal repeat; LTR; geranylgeranyltransferase; GGTI-298; small GTPase; NF-κB; p53; cell cycle
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Edwards, D.C.; McKinnon, K.M.; Fenizia, C.; Jung, K.-J.; Brady, J.N.; Pise-Masison, C.A. Inhibition of Geranylgeranyl Transferase-I Decreases Cell Viability of HTLV-1-Transformed Cells. Viruses 2011, 3, 1815-1835.

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