thromboxane-a2 and Melanoma

The GTPase RhoA is a downstream target of heterotrimeric G(13) proteins and plays key roles in cell migration and invasion. Here, we show that expression in human melanoma cells of a constitutively active, GTPase-deficient Galpha(13) form (G(alpha)(13)QL) or lysophosphatidylcholine (LPC)-promoted signaling through G(alpha)(13)-coupled receptors led to a blockade of chemokine-stimulated RhoA activation and cell invasion that was rescued by active RhoA. Melanoma cells expressing G(alpha)(13)QL or cells stimulated with LPC displayed an increase in p190RhoGAP activation, and defects in RhoA activation and invasion were recovered by knocking down p190RhoGAP expression, thus identifying this GTPase-activating protein (GAP) protein as a downstream G(alpha)(13) target that is responsible for these inhibitory responses. In addition, defective stress fiber assembly and reduced migration speed underlay inefficient invasion of G(alpha)(13)QL melanoma cells. Importantly, G(alpha)(13)QL expression in melanoma cells led to impairment in lung metastasis associated with prolonged survival in SCID mice. The data indicate that G(alpha)(13)-dependent downstream effects on RhoA activation and invasion tightly depend on cell type-specific GAP activities and that G(alpha)(13)-p190RhoGAP signaling might represent a potential target for intervention in melanoma metastasis.

Topics: Animals; Cell Line, Tumor; Chemokine CXCL12; GTP-Binding Protein alpha Subunits, G12-G13; GTP-Binding Protein alpha Subunits, Gi-Go; Guanine Nucleotide Exchange Factors; Humans; Lung Neoplasms; Lysophosphatidylcholines; Melanoma; Mice; Mice, SCID; Neoplasm Invasiveness; Proto-Oncogene Proteins c-vav; Repressor Proteins; rhoA GTP-Binding Protein; Signal Transduction; Swiss 3T3 Cells; Thromboxane A2

Platelet aggregation plays an important role in the phase of arrest of tumor cells in the microcirculation of the metastatic site in blood-borne metastasis. Hyper-aggregability of platelets, hypercoagulability and suppression of fibrinolysis accelerate the adhesion of tumor cells in the microcirculation of the target organ, but it may be inhibited by suppression of platelet aggregation, biosynthesis of thromboxane A2 and the coagulation system. Platelet aggregation is induced by not only metabolites of arachidonic acid but also factors released from tumor cells. Thromboxane A2 and prostaglandin I2 may play a role in blood-borne metastasis.

Topics: Animals; Blood Platelets; Epoprostenol; Fibrinolysis; Lung Neoplasms; Male; Melanoma; Mice; Mice, Nude; Neoplasms, Experimental; Neoplastic Cells, Circulating; Platelet Aggregation; Rats; Thromboxane A2

Topics: Alprostadil; Animals; Cell Division; Cyclic AMP; DNA Replication; Dose-Response Relationship, Drug; Epoprostenol; Male; Melanoma; Mice; Mice, Inbred C57BL; Prostaglandin Endoperoxides, Synthetic; Prostaglandins; Prostaglandins E; Thromboxane A2; Thromboxane B2; Thromboxanes