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Published on: September 28, 2020
Filamin-A is essential for dopamine d2 receptor expression and signaling in tumorous lactotrophs
Erika Peverelli1, Giovanna Mantovani, Eleonora Vitali
1Endocrinology Unit, Department of Medical Sciences, Fondazione Instituto di Ricovero e Cura a Carattere Scientifico Ca' Granda-Padiglione Granelli, University of Milan, Via Francesco Sforza, 35, 20122 Milan, Italy.
Context:
Dopamine agonists (DA) are the first choice treatment of prolactinomas. However, a subset of patients is resistant to DA, due to undefined dopamine D2 receptor (D2R) alterations. Recently, D2R was found to associate with filamin-A (FLNA), a widely expressed cytoskeleton protein with scaffolding properties, in melanoma and neuronal cells.
Objective:
The aim of the study was to investigate the role of FLNA in D2R expression and signaling in human tumorous lactotrophs and rat MMQ and GH3 cells.
Design:
We analyzed FLNA expression in a series of prolactinomas by immunohistochemistry and Western blotting. We performed FLNA silencing or transfection experiments in cultured cells from DA-sensitive or -resistant prolactinomas and in MMQ and GH3 cells, followed by analysis of D2R expression and signaling.
Results:
We demonstrated reduced FLNA and D2R expression in DA-resistant tumors. The crucial role of FLNA on D2R was demonstrated by experiments showing that: 1) FLNA silencing in DA-sensitive prolactinomas resulted in 60% reduction of D2R expression and abrogation of DA-induced inhibition of prolactin release and antiproliferative signals, these results being replicated in MMQ cells that endogenously express FLNA and D2R; and 2) FLNA overexpression in DA-resistant prolactinomas restored D2R expression and prolactin responsiveness to DA, whereas this manipulation was ineffective in GH3 cells that express FLNA but not D2R. No alteration in FLNA promoter methylation was detected, ruling out the occurrence of epigenetic FLNA silencing in DA-resistant prolactinomas.
Conclusions:
These data indicate that FLNA is crucial for D2R expression and signaling in lactotrophs, suggesting that the impaired response to DA may be related to the reduction of FLNA expression in DA-resistant prolactinomas.
Insights
Reduced filamin-A (FLNA) expression impairs dopamine D2 receptor (D2R) function in prolactinomas resistant to dopamine agonists (DA). Restoring FLNA levels can restore D2R signaling, offering potential therapeutic insights.
Area of Science:
- Endocrinology
- Molecular Cell Biology
- Oncology
Background:
- Dopamine agonists (DA) are primary treatments for prolactinomas, but some patients exhibit resistance.
- Dopamine D2 receptor (D2R) alterations are implicated in DA resistance, with recent findings linking D2R to filamin-A (FLNA).
- FLNA is a cytoskeleton protein with scaffolding functions, found in melanoma and neuronal cells.
Purpose of the Study:
- To investigate the role of FLNA in regulating D2R expression and signaling.
- To examine FLNA's function in human prolactinoma cells and rat MMQ and GH3 cell lines.
Main Methods:
- Immunohistochemistry and Western blotting were used to analyze FLNA expression in prolactinomas.
- FLNA silencing and transfection experiments were conducted in cultured cells.
- D2R expression and signaling were assessed following FLNA manipulation in DA-sensitive and -resistant prolactinoma cells, as well as MMQ and GH3 cells.
Main Results:
- DA-resistant prolactinomas showed reduced expression of both FLNA and D2R.
- FLNA silencing in DA-sensitive cells decreased D2R expression by 60% and abolished DA-induced responses.
- FLNA overexpression in DA-resistant cells restored D2R expression and DA responsiveness, but not in GH3 cells lacking D2R.
Conclusions:
- FLNA is essential for maintaining D2R expression and signaling in lactotrophs.
- Reduced FLNA expression is a potential cause of DA resistance in prolactinomas.
- Epigenetic silencing via FLNA promoter methylation was ruled out as a cause of DA resistance.
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