Caveolin-1 sensitizes rat pituitary adenoma GH3 cells to bromocriptine induced apoptosis

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.

Caveolin-1 mediates Fas–BID signaling in hyperoxia-induced apoptosis

“…Lee et al [55] also provided evidence that tyrosine-kinase signaling is regulated by tyrosine-phosphorylated Cav-1. Jiang et al [56] suggested that the phosphorylation of Cav-1 at the tyrosine Y14 terminus after bromocriptine treatment may contribute to the sensitization of apoptosis in GH3 cells that have been exposed to bromocriptine. In the same year, Shajahan et al [57] showed that the Src phosphorylation of Tyr 14 on Cav-1 regulates paclitaxel-mediated apoptosis in MCF-7 breast cancer cells.…”

Bromocriptine and Dopamine Mediate Independent and Synergistic Apoptotic Pathways in Pituitary Cells

“…Employing GH3 cells multiple reports show that DA and/or BC induce apoptosis [7,13,16,18,35]. Perhaps due to the importance of DA in pituitary physiology and homeostatic control mechanisms the characterisation of DA-mediated apoptosis has received particular recent attention in these cells [7] and also in primary rodent pituitaries and lactotrophs [14].…”

“…In common with multiple previous reports [7,13,16,17,18,31,32] a cell line model system was chosen on the basis that it circumvented likely complications associated with determining effects within the admix of cell types that comprise the normal pituitary gland. Despite the advantages afforded by this in vitro system we recognise that the concentrations of BC used in our experiments are significantly higher than C max values observed in patients following oral drug administration.…”

“…Studies of DA and of DA agonist-mediated apoptosis in the pituitary and their tumour counterparts have made extensive use of rodent and murine tumour cell lines and to a lesser extent cultured anterior pituitary cells from these species [6,7,11,12,13,14,15,16]. In particular, the rodent GH3 pituitary cell line, in the somatolactotroph cell lineage, has contributed significantly to our understanding of apoptotic mechanisms [7,13,16,17,18]; however, these cells do not express a functional D2 receptor [11,19,20]. Indeed, early studies suggested that these cells were resistant to DA- but not bromocriptine (BC)-mediated apoptosis, but that sensitivity is restored in cells transfected with a functional D2R [11].…”

Dopamine Receptor Gene (DRD1-DRD5) Expression Changes as Stress Factors Associated with Breast Cancer

“…These alterations could lead to changes in the amount of T-cells which play a key role in both cellular and hemoral immune systems (Elenkov et al, 2000). T-cells control the natural tumor cells via secretion of cytokines TNF-α (Jiang et al, 2007). Thus, the coordinated over expression of DRD2 family receptor genes enhances each other (additive effect) and leads to reduction of T-cells amount.…”