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  • Original Paper
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Inhibition of farnesyltransferase increases TGFβ type II receptor expression and enhances the responsiveness of human cancer cells to TGFβ

Oncogene volume 19, pages 5525–5533 (2000)Cite this article

Abstract

Several small GTPases of the Ras superfamily have been shown to antagonize TGFβ signaling in human tumor cell lines. Some of these GTPases are post-translationally modified by farnesylation, a lipid modification catalyzed by farnesyltransferase and required for the proteins to attach to membranes and to function. In this study, we investigated the effect of the farnesyltransferase inhibitor FTI-277 on TGFβ-regulated cell growth and transcription. Treatment of the human pancreatic tumor cell line, Panc-1, with FTI-277 enhanced the ability of TGFβ to inhibit both anchorage-dependent and -independent tumor cell growth. FTI-277 also enhanced the ability of TGFβ to induce transcription, as measured by p3TP-lux reporter activity and collagen synthesis. The enhancement of TGFβ responses by FTI-277 correlated with the stimulation of transcription and protein expression of type II TGFβ receptor (TβRII). Consequently, FTI-277-treated cells exhibited a higher level of TGFβ binding to its receptor. Thus, inhibition of protein farnesylation stimulates TβRII expression, which leads to increased TGFβ receptor binding and signaling as well as inhibition of tumor cell growth and transformation.

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Acknowledgements

The authors are grateful to Dr Carlos Muro-Cacho (Pathology Core at the Moffitt Cancer Center and Research Institute) for carefully reviewing the immunohistochemistry results and Dr J Massagué (Memorial Sloan-Kettering Cancer Center, New York, NY, USA) for providing the p3TP-Lux construct. This work was supported in part by NCI grant CA67771 to SM Sebti and AD Hamilton.

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Authors and Affiliations

  1. Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, 33612, Florida, FL, USA

    Jalila Adnane, Francisco A Bizouarn, Zhi Chen & Saïd M Sebti

  2. Molecular Oncology Program, H Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, 33612, Florida, FL, USA

    Teresita Munoz-Antonia

  3. Department of Oncology, University of South Florida, Tampa, 33612, Florida, FL, USA

    Jalila Adnane, Francisco A Bizouarn, Zhi Chen, Teresita Munoz-Antonia & Saïd M Sebti

  4. Department of Biochemistry and Molecular Biology, University of South Florida, Tampa, 33612, Florida, FL, USA

    Jalila Adnane, Francisco A Bizouarn, Zhi Chen, Teresita Munoz-Antonia & Saïd M Sebti

  5. Department of Chemistry, Yale University, New Haven, 06511, Connecticut, CT, USA

    Junko Ohkanda & Andrew D Hamilton

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  1. Jalila Adnane
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Adnane, J., Bizouarn, F., Chen, Z. et al. Inhibition of farnesyltransferase increases TGFβ type II receptor expression and enhances the responsiveness of human cancer cells to TGFβ. Oncogene 19, 5525–5533 (2000). https://doi.org/10.1038/sj.onc.1203920

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