Originally published In Press as doi:10.1074/jbc.M503763200 on July 8, 2005
J. Biol. Chem., Vol. 280, Issue 35, 31101-31108, September 2, 2005
The Farnesyl Transferase Inhibitor (FTI) SCH66336 (lonafarnib) Inhibits Rheb Farnesylation and mTOR Signaling
ROLE IN FTI ENHANCEMENT OF TAXANE AND TAMOXIFEN ANTI-TUMOR ACTIVITY*
Andrea D. Basso,
Asra Mirza,
Gongjie Liu,
Brian J. Long,
W. Robert Bishop, and
Paul Kirschmeier
From the
Department of Tumor Biology, Schering-Plough Research Institute, Kenilwort, New Jersey 07033
Lonafarnib (SCH66336 is a farnesyl transferase inhibitor (FTI) that inhibits the post-translational lipid modification of H-Ras and other farnesylated proteins. K- and N-Ras are also substrates of farnesyl transferase; however, upon treatment with FTIs, they are alternatively prenylated by geranylgeranyl transferase-1. Despite the failure to abrogate prenylation of K- and N-Ras, growth of many tumors in preclinical models is inhibited by FTIs. This suggests that the anti-proliferative action of FTIs is dependent on blocking the farnesylation of other proteins. Rheb (Ras homologue enriched in brain) is a farnesylated small GTPase that positively regulates mTOR (mammalian target of rapamycin) signaling. We found that Rheb and Rheb2 mRNA were elevated in various tumor cell lines relative to normal cells. Peptides derived from the carboxyl termini of human Rheb and Rheb2 are in vitro substrates for farnesyl transferase but not geranylgeranyl transferase-1. Rheb prenylation in cell culture was completely inhibited by SCH66336 indicating a lack of alternative prenylation. SCH66336treatment also inhibited the phosphorylation of S6 ribosomal protein, a downstream target of Rheb and mTOR signaling. SCH66336did not inhibit S6 phosphorylation in cells expressing Rheb-CSVL, a mutant construct of Rheb designed to be geranylgeranylated. Importantly, expression of Rheb-CSVL also abrogated SCH66336enhancement of tamoxifen- and docetaxel-induced apoptosis in MCF-7 breast cancer cells and ES-2 ovarian cancer cells, respectively. Further, inhibition of Rheb signaling by rapamycin treatment, small interfering RNA, or dominant negative Rheb enhanced tamoxifen- and docetaxel-induced apoptosis, similar to FTI treatment. These studies demonstrated that Rheb is modified by farnesylation, is not a substrate for alternative prenylation, and plays a role in SCH66336enhancement of the anti-tumor response to other chemotherapeutics.
Received for publication, April 6, 2005
, and in revised form, June 20, 2005.
* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Schering-Plough Research Institute, 2015 Galloping Hill Rd., K-15-4950, Kenilworth, NJ 07033. Tel.: 908-740-7327; Fax: 908-740-3918; E-mail: paul.kirschmeier{at}spcorp.com.
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Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.
