Dopamine blocks stress-mediated ovarian carcinoma growth.
Title | Dopamine blocks stress-mediated ovarian carcinoma growth. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Moreno-Smith M, Lu C, Shahzad MMK, Pena GNArmaiz, Allen JK, Stone RL, Mangala LS, Han HDong, Kim HSun, Farley D, Berestein GLopez, Cole SW, Lutgendorf SK, Sood AK |
Journal | Clin Cancer Res |
Volume | 17 |
Issue | 11 |
Pagination | 3649-59 |
Date Published | 2011 Jun 1 |
ISSN | 1078-0432 |
Keywords | Animals, Cell Line, Tumor, Cell Proliferation, Dopamine, Female, Humans, Mice, Mice, Inbred C57BL, Mice, Nude, Neovascularization, Pathologic, Ovarian Neoplasms, Receptors, Dopamine, Stress, Physiological, Tumor Microenvironment |
Abstract | PURPOSE: Increased adrenergic activity in response to chronic stress is known to promote tumor growth by stimulating the tumor microenvironment. The focus of the current study was to determine whether dopamine, an inhibitory catecholamine, could block the effects of chronic stress on tumor growth. EXPERIMENTAL DESIGN: Expression of dopamine receptors (DR1-DR5) was analyzed by reverse transcriptase-PCR and by Western blotting. In vitro effects of dopamine on cell viability, apoptosis, and migration were examined. For in vivo therapy, murine and human DR2-siRNAs were incorporated into chitosan nanoparticles (CH-NP). RESULTS: In this model of chronic stress, tumoral norepinephrine levels remained elevated whereas dopamine levels were significantly decreased compared with nonstressed animals. Daily restraint stress resulted in significantly increased tumor growth in both immunodeficient (SKOV3ip1 and HeyA8) and immunocompetent (ID8) ovarian cancer models. This increase was completely blocked with daily dopamine treatment. Dopamine treatment also blocked the stress-induced increase in angiogenesis. Endothelial and ovarian cancer cells expressed all dopamine receptors except for the lack of DR3 expression in ovarian cancer cells. DR2 was responsible for the inhibitory effects of dopamine on tumor growth and microvessel density as well as the stimulatory effect on apoptosis, as the DR2 antagonist eticlopride reversed these effects. Dopamine significantly inhibited cell viability and stimulated apoptosis in vitro. Moreover, dopamine reduced cyclic AMP levels and inhibited norepinephrine and vascular permeability factor/VEGF-induced Src kinase activation. CONCLUSIONS: Dopamine depletion under chronic stress conditions creates a permissive microenvironment for tumor growth that can be reversed by dopamine replacement. |
DOI | 10.1158/1078-0432.CCR-10-2441 |
Alternate Journal | Clin. Cancer Res. |
PubMed ID | 21531818 |
PubMed Central ID | PMC3107884 |
Grant List | CA109298 / CA / NCI NIH HHS / United States CA110793 / CA / NCI NIH HHS / United States CA128797 / CA / NCI NIH HHS / United States HD050128 / HD / NICHD NIH HHS / United States K12 HD050128-05 / HD / NICHD NIH HHS / United States P50 CA 083639 / CA / NCI NIH HHS / United States P50 CA083639 / CA / NCI NIH HHS / United States P50 CA083639-09 / CA / NCI NIH HHS / United States R01 CA109298 / CA / NCI NIH HHS / United States R01 CA109298-08 / CA / NCI NIH HHS / United States R01 CA110793 / CA / NCI NIH HHS / United States R01 CA110793-05S1 / CA / NCI NIH HHS / United States R01 CA128797 / CA / NCI NIH HHS / United States R01 CA128797-05 / CA / NCI NIH HHS / United States R01 CA140933 / CA / NCI NIH HHS / United States RC2 GM092599 / GM / NIGMS NIH HHS / United States RC2 GM092599-03 / GM / NIGMS NIH HHS / United States RC2GM092599 / GM / NIGMS NIH HHS / United States T32 CA101642 / CA / NCI NIH HHS / United States T32 CA101642 / CA / NCI NIH HHS / United States T32 CA101642-05 / CA / NCI NIH HHS / United States U54 CA151668 / CA / NCI NIH HHS / United States U54 CA151668-02 / CA / NCI NIH HHS / United States U54CA151668 / CA / NCI NIH HHS / United States |