The main findings of this study are that dopamine significantly reduces stress-mediated cancer growth in ovarian carcinoma. Our data strongly suggest that dopamine retards tumor growth by inhibiting tumor angiogenesis and stimulating tumor cell apoptosis. In addition, we provide the first evidence that dopamine is able to block the stimulatory effects of chronic stress on cancer growth.
The physiological actions of dopamine are mediated by at least 5 distinct G-protein-coupled receptor subtypes. (26
). Two DR1-like receptor subtypes (DR1 and DR5) couple to the G protein Gs, activate adenylate cyclase and increase cAMP levels. The other receptor subtypes belong to the DR2-like subfamily (DR2, DR3 and DR4) and are prototypic of G protein-coupled receptors that inhibit adenylate cyclase and decrease cAMP production. The ovarian non-transformed, cancer and endothelial cells tested in this work showed expression of DR1 and DR2-like dopamine receptors, indicating that dopamine might regulate stimulatory and/or inhibitory processes in these cells.
Dysfunction of dopaminergic system is known to be associated with various disorders, including schizophrenia and Parkinson’s disease (28
). The consequences of dopamine dysfunction indicate the importance of maintaining dopamine functionality through homeostatic mechanisms based on the delicate balance between synthesis, storage, release, metabolism and reuptake (28
). A decrease in dopamine in the brain has been implicated as the cause of Parkinson’s disease. In contrast, it is argued that a functional excess of DA or oversensitivity of certain DR’s is one of the causal factors in schizophrenia (29
). Interestingly, the incidence of cancer in patients with schizophrenia has been reported to be lower than in the general population (30
). Whether this reduced incidence is related to hyperactive dopaminergic system is not known.
It has been demonstrated that dopamine concentrations are lower in the tumor microenvironment compared to normal tissues (11
). These findings prompted us to consider whether the increases in tumor growth and angiogenesis may result from a permissive microenvironment created by a relative shift toward growth-promoting catecholamines. In the present study, we demonstrate that dopamine blocks stress induced tumor growth by activating DR2. The central role of DR2 was confirmed with the DR2-antagonist eticlopride in combination therapy with dopamine, as well as with siRNA targeted against murine or human DR2. The dopamine-suppressing effect on tumor growth in our stress models was significantly blunted by DR2 gene silencing. These findings indicate that dopamine targets both host murine endothelial cells and human cancer cells through DR2 to exert its growth suppressive effects. Our results are supported by the reported growth inhibitory effects of dopamine under non-stress conditions (7
Our data also indicate that dopamine, via
DR2, blocked the VPF/VEGF or norepinephrine mediated invasion of ovarian cancer cells. The inhibitory effects of dopamine on cell invasion would explain, in part, the in vivo
blocking effect of dopamine on tumor progression and metastasis under chronic stress. Our in vitro
studies demonstrate that dopamine decreases viability not only of endothelial cells, as previously described, (7
) but also of ovarian cancer cells. These results were further confirmed using in vivo
models of ovarian carcinoma. The dual cell targeting (endothelial and tumor cells) of dopamine in the tumor microenvironment underlines the significance of dopamine as a potential modality to block the growth stimulatory effects of chronic stress.
Dopamine and DR2-agonists have been used for many years for the treatment of Parkinson’s disease and hyperprolactinemia (35
) as well as for management of cardiovascular disorders and renal dysfunction.(37
). Dopamine agonists such as bromocriptine mesylate (Parlodel, oral) have also been used clinically to treat hyperprolactinemia and are well tolerated (39
). Furthermore, effective shrinkage of prolactinomas has been observed after injection of long-acting form of Parlodel (40
). Such agents may represent a new strategy for blocking the effects of chronic stress on tumor growth. With such therapies, however, some adverse reactions such as nausea, hallucinations, and orthostatic hypotension have been reported and would require careful monitoring.
To identify the signaling pathways by which dopamine affects endothelial and ovarian cancer cell function, we examined the effects of dopamine on phophorylation and activation of various effectors in the metastatic cascade. In MOEC, dopamine inhibited VEGF-induced phophorylation and activaton of Src kinase. In addition, dopamine reversed NE-stimulated Src-phosphorylation. Src is a key mediator for multiple signaling pathways that regulate critical cellular functions (41
). In ovarian cancer, Src has been shown to play a functional role in cancer cell invasion and angiogenesis (42
). Src is also a regulator of VEGF-mediated vascular permeability (43
). Recent studies in HUVEC have shown that dopamine reduces VEGF-mediated permeability by inhibiting VEGF-induced Src activation (44
). These studies coupled with our data implicate blockade of Src activation as a key mediator of the inhibitory effects of dopamine on ovarian cancer growth.
Overall, our data suggest that dopamine inhibits stress hormone stimulated Src activation in endothelial and ovarian cancer cells. Moreover, we conclude that dopamine-replacement effectively counteracts the stimulatory effects of norepinephrine on ovarian cancer growth during chronic stress. Considering the stimulatory effects of chronic stress on cancer growth (6
), our findings implicate dopamine as a potential therapeutic strategy for blocking the deleterious effects of chronic stress.