Farnesyl transferase inhibitor FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation

Lee,Kyung  Hun; Koh,Minsoo; Moon,Aree

doi:10.3892/ol.2016.4837

Farnesyl transferase inhibitor FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation

Authors:
- Kyung Hun Lee
- Minsoo Koh
- Aree Moon
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Affiliations: Duksung Innovative Drug Center, College of Pharmacy, Duksung Women's University, Seoul 132‑714, Republic of Korea
Published online on: July 11, 2016 https://doi.org/10.3892/ol.2016.4837
Pages: 2222-2226

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Abstract

Hyperactive Ras promotes proliferation and malignant phenotypic conversion of cells in cancer. Ras protein must be associated with cellular membranes for its oncogenic activities through post-translational modifications, including farnesylation. Farnesyltransferase (FTase) is essential for H‑Ras membrane targeting, and H‑Ras, but not N‑Ras, has been demonstrated to cause an invasive phenotype in MCF10A breast epithelial cells. In the present study, it was observed that an FTase inhibitor (FTI), FTI-277, blocked epidermal growth factor (EGF)-induced H‑Ras activation, but not N‑Ras activation in MDA-MB-231 cells, which express wild‑type H-Ras and N-Ras. FTI-277 exerted a more potent inhibitory effect on the proliferation of H-Ras-MCF10A cells and Hs578T breast cancer cells expressing an active mutant of H‑Ras than that of MDA-MB-231 cells. The invasive/migratory phenotypes of the H‑Ras‑MCF10A and Hs578T cells were effectively inhibited by FTI-277 treatment. By contrast, FTI‑277 did not affect the invasive/migratory phenotypes of MDA‑MB‑231 cells. However, the EGF‑induced invasion of MDA‑MB‑231 cells was decreased by FTI‑277, implicating that FTI‑277 inhibits breast cell invasion and migration by blocking H‑Ras activation. Taken together, the results of the present study suggest that FTase inhibition by FTI‑277 may be an effective strategy for targeting H-Ras-mediated proliferation, migration and invasion of breast cells.

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