HO-3867, a synthetic compound, inhibits the migration and invasion of ovarian carcinoma cells through downregulation of fatty acid synthase and focal adhesion kinase

Karuppaiyah Selvendiran, Shabnam Ahmed, Alex Dayton, Yazhini Ravi, M. Lakshmi Kuppusamy, Anna Bratasz, Brian K. Rivera, Tamás Kálai, Kálmán Hideg, Periannan Kuppusamy

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Abstract

Fatty acid synthase (FAS) and focal adhesion kinase (FAK), which are overexpressed in a variety of human epithelial tumors, play a key role in the migration and invasion of cancer cells. Hence, strategies targeted at inhibiting the FAS/FAK proteins may have therapeutic potential for cancer treatment. The goal of the present study was to determine the effect of HO-3867, a synthetic compound, on the migratory ability of ovarian cancer cells and to understand the mechanistic pathways including the involvement of FAS, FAK, and associated signaling proteins. The study was done using two established human ovarian cancer cell lines, A2780 and SKOV3. Incubation with 10 μmol/L HO-3867 for 24 hours significantly inhibited the native as well as the vascular endothelial growth factor (VEGF)-mediated migration and invasion of the cells. HO-3867 significantly attenuated FAS and FAK protein levels apparently through accelerated ubiquitin-dependent degradation, as shown by a clear downregulation of isopeptidase USP2a. Exposure of cells to HO-3867 also significantly inhibited FAS activity and mRNA levels and a number of downstream proteins, including phospho-extracellular signal-regulated kinase 1/2, phospho-human epidermal growth factor receptor 1, sterol regulatory element binding protein 1, VEGF, and matrix metalloproteinase 2. Western blot and immunohistochemical analyses of A2780 xenograft tumors in mice treated with HO-3867 showed significant reduction in FAS, FAK, VEGF, and downstream protein levels when compared with the untreated control. Collectively, the results showed that HO-3867 suppressed the migration and invasion of ovarian cancer cells by inhibiting the expression or activity of FAS and FAK proteins. The study suggests that molecular targeting of FAS and FAK by HO-3867 may be a potential strategy for ovarian cancer therapy.

Original languageEnglish (US)
Pages (from-to)1188-1197
Number of pages10
JournalMolecular Cancer Research
Volume8
Issue number9
DOIs
StatePublished - Sep 1 2010

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Fatty Acid Synthases
Focal Adhesion Protein-Tyrosine Kinases
Down-Regulation
Carcinoma
Ovarian Neoplasms
Vascular Endothelial Growth Factor A
Proteins
Neoplasms
Sterol Regulatory Element Binding Protein 1
Mitogen-Activated Protein Kinase 3
(3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one)
Mitogen-Activated Protein Kinase 1
Matrix Metalloproteinase 2
Ubiquitin
Epidermal Growth Factor Receptor
Heterografts
Cell Movement
Western Blotting
Cell Line
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

HO-3867, a synthetic compound, inhibits the migration and invasion of ovarian carcinoma cells through downregulation of fatty acid synthase and focal adhesion kinase. / Selvendiran, Karuppaiyah; Ahmed, Shabnam; Dayton, Alex; Ravi, Yazhini; Kuppusamy, M. Lakshmi; Bratasz, Anna; Rivera, Brian K.; Kálai, Tamás; Hideg, Kálmán; Kuppusamy, Periannan.

In: Molecular Cancer Research, Vol. 8, No. 9, 01.09.2010, p. 1188-1197.

Research output: Contribution to journalArticle

Selvendiran, Karuppaiyah ; Ahmed, Shabnam ; Dayton, Alex ; Ravi, Yazhini ; Kuppusamy, M. Lakshmi ; Bratasz, Anna ; Rivera, Brian K. ; Kálai, Tamás ; Hideg, Kálmán ; Kuppusamy, Periannan. / HO-3867, a synthetic compound, inhibits the migration and invasion of ovarian carcinoma cells through downregulation of fatty acid synthase and focal adhesion kinase. In: Molecular Cancer Research. 2010 ; Vol. 8, No. 9. pp. 1188-1197.
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abstract = "Fatty acid synthase (FAS) and focal adhesion kinase (FAK), which are overexpressed in a variety of human epithelial tumors, play a key role in the migration and invasion of cancer cells. Hence, strategies targeted at inhibiting the FAS/FAK proteins may have therapeutic potential for cancer treatment. The goal of the present study was to determine the effect of HO-3867, a synthetic compound, on the migratory ability of ovarian cancer cells and to understand the mechanistic pathways including the involvement of FAS, FAK, and associated signaling proteins. The study was done using two established human ovarian cancer cell lines, A2780 and SKOV3. Incubation with 10 μmol/L HO-3867 for 24 hours significantly inhibited the native as well as the vascular endothelial growth factor (VEGF)-mediated migration and invasion of the cells. HO-3867 significantly attenuated FAS and FAK protein levels apparently through accelerated ubiquitin-dependent degradation, as shown by a clear downregulation of isopeptidase USP2a. Exposure of cells to HO-3867 also significantly inhibited FAS activity and mRNA levels and a number of downstream proteins, including phospho-extracellular signal-regulated kinase 1/2, phospho-human epidermal growth factor receptor 1, sterol regulatory element binding protein 1, VEGF, and matrix metalloproteinase 2. Western blot and immunohistochemical analyses of A2780 xenograft tumors in mice treated with HO-3867 showed significant reduction in FAS, FAK, VEGF, and downstream protein levels when compared with the untreated control. Collectively, the results showed that HO-3867 suppressed the migration and invasion of ovarian cancer cells by inhibiting the expression or activity of FAS and FAK proteins. The study suggests that molecular targeting of FAS and FAK by HO-3867 may be a potential strategy for ovarian cancer therapy.",
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AU - Dayton, Alex

AU - Ravi, Yazhini

AU - Kuppusamy, M. Lakshmi

AU - Bratasz, Anna

AU - Rivera, Brian K.

AU - Kálai, Tamás

AU - Hideg, Kálmán

AU - Kuppusamy, Periannan

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