Abstract
BackgroundProlactinoma is the most frequent pituitary tumor in humans. The dopamine D2 receptor agonist bromocriptine has been widely used clinically to treat human breast tumor and prolactinoma through inhibition of hyperprolactinemia and induction of tumor cell apoptosis, respectively, but the molecular mechanism of bromocriptine induction of pituitary tumor apoptosis remains unclear. Caveolin-1 is a membrane-anchored protein enriched on caveolae, inverted flask-shaped invaginations on plasma membranes where signal transduction molecules are concentrated. Currently, caveolin-1 is thought to be a negative regulator of cellular proliferation and an enhancer of apoptosis by blocking signal transduction between cell surface membrane receptors and intracellular signaling protein cascades. Rat pituitary adenoma GH3 cells, which express endogenous caveolin-1, exhibit increased apoptosis and shrinkage after exposure to bromocriptine. Hence, the GH3 cell line is an ideal model for studying the molecular action of bromocriptine on prolactinoma.ResultsThe expression of endogenous caveolin-1 in GH3 cells was elevated after bromocriptine treatment. Transiently expressed mouse recombinant caveolin-1 induced apoptosis in GH3 cells by enhancing the activity of caspase 8. Significantly, caveolin-1 induction of GH3 cell apoptosis was sensitized by the administration of bromocriptine. Phosphorylation of caveolin-1 at tyrosine 14 was enhanced after bromocriptine treatment, suggesting that bromocriptine-induced phosphorylation of caveolin-1 may contribute to sensitization of apoptosis in GH3 cells exposed to bromocriptine.ConclusionOur results reveal that caveolin-1 increases sensitivity for apoptosis induction in pituitary adenoma GH3 cells and may contribute to tumor shrinkage after clinical bromocriptine treatment.
Highlights
Prolactinoma is the most frequent pituitary tumor in humans
As bromocriptine stimulates GH3 cell shrinkage and apoptosis, we hypothesized that bromocriptine treatment would induce GH3 cell apoptosis via caveolin-1
Twenty-four kDa endogenous caveolin-1 expressed in the A431 cell line, and recognized by an anticaveolin-1 antibody, was used as the positive control in Western blotting (Fig. 1A,b)
Summary
The dopamine D2 receptor agonist bromocriptine has been widely used clinically to treat human breast tumor and prolactinoma through inhibition of hyperprolactinemia and induction of tumor cell apoptosis, respectively, but the molecular mechanism of bromocriptine induction of pituitary tumor apoptosis remains unclear. Rat pituitary adenoma GH3 cells, which express endogenous caveolin-1, exhibit increased apoptosis and shrinkage after exposure to bromocriptine. The GH3 cell line is an ideal model for studying the molecular action of bromocriptine on prolactinoma. Prolactinomas, prolactin-secreting pituitary adenomas, are the most frequently found functional pituitary tumors in humans. Bromocriptine is commonly chosen as a therapeutic agent for patients with prolactinomas or other pituitary adenomas; bromocriptine binds to the dopamine D2 receptor on pituitary epithelial cells to inhibit prolactin secretion [2]. Long-term incubation of GH3 with bromocriptine induces cell apoptosis [4]
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