NGF-Enhanced Vasculogenic Properties of Epithelial Ovarian Cancer Cells Is Reduced by Inhibition of the COX-2/PGE2 Signaling Axis
by
Maritza P. Garrido 1,2,†, Iván Hurtado 1,2,†
, Manuel Valenzuela-Valderrama 3,4, Renato Salvatierra 1, Andrea Hernández 1, Margarita Vega 1,2, Alberto Selman 2, Andrew F. G. Quest 4,5,* and Carmen Romero 1,2,4,*
Maritza P. Garrido 1,2,†, Iván Hurtado 1,2,†, Manuel Valenzuela-Valderrama 3,4, Renato Salvatierra 1, Andrea Hernández 1, Margarita Vega 1,2, Alberto Selman 2, Andrew F. G. Quest 4,5,* and Carmen Romero 1,2,4,*
1
Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile
2
Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
3
Laboratorio de Microbiología Celular. Instituto de Investigación e Innovación en Salud. Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago 8320000, Chile
4
Advanced Center for Chronic Diseases (ACCDIS), Santiago 8380000, Chile
5
Laboratorio de Comunicaciones Celulares, Centro de estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2019, 11(12), 1970; https://doi.org/10.3390/cancers11121970
Received: 28 October 2019 / Revised: 17 November 2019 / Accepted: 19 November 2019 / Published: 7 December 2019
Epithelial ovarian cancer (EOC) is a lethal gynecological neoplasia characterized by extensive angiogenesis and overexpression of nerve growth factor (NGF). Here, we investigated the mechanism by which NGF increases vascular endothelial growth factor (VEGF) expression and the vasculogenic potential of EOC cells, as well as the contribution of the cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) signaling axis to these events. EOC biopsies and ovarian cell lines were used to determine COX-2 and PGE2 levels, as well as those of the potentially pro-angiogenic proteins c-MYC (a member of the Myc transcription factors family), survivin, and β-catenin. We observed that COX-2 and survivin protein levels increased during EOC progression. In the EOC cell lines, NGF increased the COX-2 and PGE2 levels. In addition, NGF increased survivin, c-MYC, and VEGF protein levels, as well as the transcriptional activity of c-MYC and β-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef) in a Tropomyosin receptor kinase A (TRKA)-dependent manner. Also, COX-2 inhibition prevented the NGF-induced increases in these proteins and reduced the angiogenic score of endothelial cells stimulated with conditioned media from EOC cells. In summary, we show here that the pro-angiogenic effect of NGF in EOC depends on the COX-2/PGE2 signaling axis. Thus, inhibition COX-2/PGE2 signaling will likely be beneficial in the treatment of EOC.
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Keywords:
NGF; epithelial ovarian cancer; COX-2/PGE2; vasculogenesis; VEGF; c-MYC; survivin; beta-catenin
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MDPI and ACS Style
Garrido, M.P.; Hurtado, I.; Valenzuela-Valderrama, M.; Salvatierra, R.; Hernández, A.; Vega, M.; Selman, A.; Quest, A.F.G.; Romero, C. NGF-Enhanced Vasculogenic Properties of Epithelial Ovarian Cancer Cells Is Reduced by Inhibition of the COX-2/PGE2 Signaling Axis. Cancers 2019, 11, 1970.
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