NGF/TRKA Promotes ADAM17-Dependent Cleavage of P75 in Ovarian Cells: Elucidating a Pro-Tumoral Mechanism
Nerve growth factor (NGF) and its high-affinity receptor TRKA are overexpressed in epithelial ovarian cancer (EOC) displaying a crucial role in the disease progression. Otherwise, NGF interacts with its low-affinity receptor P75, activating pro-apoptotic pathways. In neurons, P75 could be cleaved by...
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MDPI AG
2022-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/4/2124 |
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| author | Maritza P. Garrido Christopher Vallejos Silvanna Girardi Fernando Gabler Alberto Selman Fernanda López Margarita Vega Carmen Romero |
| author_facet | Maritza P. Garrido Christopher Vallejos Silvanna Girardi Fernando Gabler Alberto Selman Fernanda López Margarita Vega Carmen Romero |
| author_sort | Maritza P. Garrido |
| collection | DOAJ |
| description | Nerve growth factor (NGF) and its high-affinity receptor TRKA are overexpressed in epithelial ovarian cancer (EOC) displaying a crucial role in the disease progression. Otherwise, NGF interacts with its low-affinity receptor P75, activating pro-apoptotic pathways. In neurons, P75 could be cleaved by metalloproteinases (α and γ-secretases), leading to a decrease in P75 signaling. Therefore, this study aimed to evaluate whether the shedding of P75 occurs in EOC cells and whether NGF/TRKA could promote the cleavage of the P75 receptor. The immunodetection of the α-secretase, ADAM17, TRKA, P75, and P75 fragments was assessed by immunohisto/cytochemistry and Western blot in biopsies and ovarian cell lines. The TRKA and secretases’ inhibition was performed using specific inhibitors. The results show that P75 immunodetection decreased during EOC progression and was negatively correlated with the presence of TRKA in EOC biopsies. NGF/TRKA increases ADAM17 levels and the fragments of P75 in ovarian cells. This effect is abolished when cells are previously treated with ADAM17, γ-secretase, and TRKA inhibitors. These results indicate that NGF/TRKA promotes the shedding of P75, involving the activation of secretases such as ADAM17. Since ADAM17 has been proposed as a screening marker for early detection of EOC, our results contribute to understanding better the role of ADAM17 and NGF/TRKA in EOC pathogenesis, which includes the NGF/TRKA-mediated cleavage of P75. |
| first_indexed | 2024-03-09T21:45:04Z |
| format | Article |
| id | doaj.art-75fabf96364b41428905089db14655ab |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:45:04Z |
| publishDate | 2022-02-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-75fabf96364b41428905089db14655ab2023-11-23T20:20:20ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-02-01234212410.3390/ijms23042124NGF/TRKA Promotes ADAM17-Dependent Cleavage of P75 in Ovarian Cells: Elucidating a Pro-Tumoral MechanismMaritza P. Garrido0Christopher Vallejos1Silvanna Girardi2Fernando Gabler3Alberto Selman4Fernanda López5Margarita Vega6Carmen Romero7Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, ChileLaboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, ChileLaboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, ChileDepartamento de Patología, Escuela de Medicina, Hospital San Borja Arriarán, Universidad de Chile, Santiago 8360160, ChileDepartamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago 8380453, ChileLaboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, ChileLaboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, ChileLaboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, ChileNerve growth factor (NGF) and its high-affinity receptor TRKA are overexpressed in epithelial ovarian cancer (EOC) displaying a crucial role in the disease progression. Otherwise, NGF interacts with its low-affinity receptor P75, activating pro-apoptotic pathways. In neurons, P75 could be cleaved by metalloproteinases (α and γ-secretases), leading to a decrease in P75 signaling. Therefore, this study aimed to evaluate whether the shedding of P75 occurs in EOC cells and whether NGF/TRKA could promote the cleavage of the P75 receptor. The immunodetection of the α-secretase, ADAM17, TRKA, P75, and P75 fragments was assessed by immunohisto/cytochemistry and Western blot in biopsies and ovarian cell lines. The TRKA and secretases’ inhibition was performed using specific inhibitors. The results show that P75 immunodetection decreased during EOC progression and was negatively correlated with the presence of TRKA in EOC biopsies. NGF/TRKA increases ADAM17 levels and the fragments of P75 in ovarian cells. This effect is abolished when cells are previously treated with ADAM17, γ-secretase, and TRKA inhibitors. These results indicate that NGF/TRKA promotes the shedding of P75, involving the activation of secretases such as ADAM17. Since ADAM17 has been proposed as a screening marker for early detection of EOC, our results contribute to understanding better the role of ADAM17 and NGF/TRKA in EOC pathogenesis, which includes the NGF/TRKA-mediated cleavage of P75.https://www.mdpi.com/1422-0067/23/4/2124NGFTRKAP75ADAM17secretaseovarian cancer |
| spellingShingle | Maritza P. Garrido Christopher Vallejos Silvanna Girardi Fernando Gabler Alberto Selman Fernanda López Margarita Vega Carmen Romero NGF/TRKA Promotes ADAM17-Dependent Cleavage of P75 in Ovarian Cells: Elucidating a Pro-Tumoral Mechanism International Journal of Molecular Sciences NGF TRKA P75 ADAM17 secretase ovarian cancer |
| title | NGF/TRKA Promotes ADAM17-Dependent Cleavage of P75 in Ovarian Cells: Elucidating a Pro-Tumoral Mechanism |
| title_full | NGF/TRKA Promotes ADAM17-Dependent Cleavage of P75 in Ovarian Cells: Elucidating a Pro-Tumoral Mechanism |
| title_fullStr | NGF/TRKA Promotes ADAM17-Dependent Cleavage of P75 in Ovarian Cells: Elucidating a Pro-Tumoral Mechanism |
| title_full_unstemmed | NGF/TRKA Promotes ADAM17-Dependent Cleavage of P75 in Ovarian Cells: Elucidating a Pro-Tumoral Mechanism |
| title_short | NGF/TRKA Promotes ADAM17-Dependent Cleavage of P75 in Ovarian Cells: Elucidating a Pro-Tumoral Mechanism |
| title_sort | ngf trka promotes adam17 dependent cleavage of p75 in ovarian cells elucidating a pro tumoral mechanism |
| topic | NGF TRKA P75 ADAM17 secretase ovarian cancer |
| url | https://www.mdpi.com/1422-0067/23/4/2124 |
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