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Title: Role for protein geranylgeranylation in adult T-cell leukemia cell survival

Abstract

Adult T-cell leukemia (ATL) is a fatal lymphoproliferative disease that develops in human T-cell leukemia virus type I (HTLV-I)-infected individuals. Despite the accumulating knowledge of the molecular biology of HTLV-I-infected cells, effective therapeutic strategies remain to be established. Recent reports showed that the hydroxyl-3-methylglutaryl (HMG)-CoA reductase inhibitor statins have anti-proliferative and apoptotic effects on certain tumor cells through inhibition of protein prenylation. Here, we report that statins hinder the survival of ATL cells and induce apoptotic cell death. Inhibition of protein geranylgeranylation is responsible for these effects, since simultaneous treatment with isoprenoid precursors, geranylgeranyl pyrophosphate or farnesyl pyrophosphate, but not a cholesterol precursor squalene, restored the viability of ATL cells. Simvastatin inhibited geranylgeranylation of small GTPases Rab5B and Rac1 in ATL cells, and a geranylgeranyl transferase inhibitor GGTI-298 reduced ATL cell viability more efficiently than a farnesyl transferase inhibitor FTI-277. These results not only unveil an important role for protein geranylgeranylation in ATL cell survival, but also implicate therapeutic potentials of statins in the treatment of ATL.

Authors:
 [1]; ;  [1];  [2]; ;  [1]; ;  [2];  [1];  [1]
  1. Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Bunkyo-ku, Tokyo 113-8510 (Japan)
  2. Department of Hematology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo (Japan)
Publication Date:
OSTI Identifier:
21176155
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 315; Journal Issue: 2; Other Information: DOI: 10.1016/j.yexcr.2008.10.010; PII: S0014-4827(08)00426-6; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CHOLESTEROL; HYDROXIDES; INHIBITION; LEUKEMIA; LEUKEMIA VIRUSES; MOLECULAR BIOLOGY; PROTEINS; PYROPHOSPHATES; SQUALENE; TUMOR CELLS

Citation Formats

Nonaka, Mizuho, Retrovirus Research Unit, RIKEN, Saitama, Uota, Shin, Saitoh, Yasunori, Takahashi, Mayumi, Sugimoto, Haruyo, Amet, Tohti, Arai, Ayako, Miura, Osamu, Yamamoto, Naoki, AIDS Research Center, National Institute of Infectious Diseases, Tokyo, and Yamaoka, Shoji. Role for protein geranylgeranylation in adult T-cell leukemia cell survival. United States: N. p., 2009. Web. doi:10.1016/j.yexcr.2008.10.010.
Nonaka, Mizuho, Retrovirus Research Unit, RIKEN, Saitama, Uota, Shin, Saitoh, Yasunori, Takahashi, Mayumi, Sugimoto, Haruyo, Amet, Tohti, Arai, Ayako, Miura, Osamu, Yamamoto, Naoki, AIDS Research Center, National Institute of Infectious Diseases, Tokyo, & Yamaoka, Shoji. Role for protein geranylgeranylation in adult T-cell leukemia cell survival. United States. https://doi.org/10.1016/j.yexcr.2008.10.010
Nonaka, Mizuho, Retrovirus Research Unit, RIKEN, Saitama, Uota, Shin, Saitoh, Yasunori, Takahashi, Mayumi, Sugimoto, Haruyo, Amet, Tohti, Arai, Ayako, Miura, Osamu, Yamamoto, Naoki, AIDS Research Center, National Institute of Infectious Diseases, Tokyo, and Yamaoka, Shoji. 2009. "Role for protein geranylgeranylation in adult T-cell leukemia cell survival". United States. https://doi.org/10.1016/j.yexcr.2008.10.010.
@article{osti_21176155,
title = {Role for protein geranylgeranylation in adult T-cell leukemia cell survival},
author = {Nonaka, Mizuho and Retrovirus Research Unit, RIKEN, Saitama and Uota, Shin and Saitoh, Yasunori and Takahashi, Mayumi and Sugimoto, Haruyo and Amet, Tohti and Arai, Ayako and Miura, Osamu and Yamamoto, Naoki and AIDS Research Center, National Institute of Infectious Diseases, Tokyo and Yamaoka, Shoji},
abstractNote = {Adult T-cell leukemia (ATL) is a fatal lymphoproliferative disease that develops in human T-cell leukemia virus type I (HTLV-I)-infected individuals. Despite the accumulating knowledge of the molecular biology of HTLV-I-infected cells, effective therapeutic strategies remain to be established. Recent reports showed that the hydroxyl-3-methylglutaryl (HMG)-CoA reductase inhibitor statins have anti-proliferative and apoptotic effects on certain tumor cells through inhibition of protein prenylation. Here, we report that statins hinder the survival of ATL cells and induce apoptotic cell death. Inhibition of protein geranylgeranylation is responsible for these effects, since simultaneous treatment with isoprenoid precursors, geranylgeranyl pyrophosphate or farnesyl pyrophosphate, but not a cholesterol precursor squalene, restored the viability of ATL cells. Simvastatin inhibited geranylgeranylation of small GTPases Rab5B and Rac1 in ATL cells, and a geranylgeranyl transferase inhibitor GGTI-298 reduced ATL cell viability more efficiently than a farnesyl transferase inhibitor FTI-277. These results not only unveil an important role for protein geranylgeranylation in ATL cell survival, but also implicate therapeutic potentials of statins in the treatment of ATL.},
doi = {10.1016/j.yexcr.2008.10.010},
url = {https://www.osti.gov/biblio/21176155}, journal = {Experimental Cell Research},
issn = {0014-4827},
number = 2,
volume = 315,
place = {United States},
year = {Thu Jan 15 00:00:00 EST 2009},
month = {Thu Jan 15 00:00:00 EST 2009}
}