The thromboxane synthase and receptor signaling pathway in cancer: an emerging paradigm in cancer progression and metastasis

Abstract

Thromboxane A(2) (TXA(2)) is a biologically active metabolite of arachidonic acid formed by the action of the terminal synthase, thromboxane A(2) synthase (TXA(2)S), on prostaglandin endoperoxide (PGH(2)). TXA(2) is responsible for multiple biological processes through its cell surface receptor, the T-prostanoid (TP) receptor. Thromboxane A(2) synthase and TP are the two necessary components for the functioning of this potent bioactive lipid. Thromboxane A(2) is widely implicated in a range of cardiovascular diseases, owing to its acute and chronic effects in promoting platelet aggregation, vasoconstriction, and proliferation. In recent years, additional functional roles for both TXA(2)S and TP in cancer progression have been indicated. Increased cyclooxygenase (COX)-2 expression has been described in a variety of human cancers, which has focused attention on TXA(2) as a downstream metabolite of the COX-2-derived PGH(2). Several studies suggest potential involvement of TXA(2)S and TP in tumor progression, especially tumor cell proliferation, migration, and invasion that are key steps in cancer progression. In addition, the regulation of neovascularization by TP has been identified as a potent source of control during oncogenesis. There have been several recent reviews of TXA(2)S and TP but thus far none have discussed its role in cancer progression and metastasis in depth. This review will focus on some of the more recent findings and advances with a significant emphasis on understanding the functional role of TXA(2)S and TP in cancer progression and metastasis.

Fig. 1

Generation of the prostanoids through metabolism of arachidonic acid. Arachidonic acid can be metabolized into different bioactive lipids by one of three distinct signaling pathways; the cyclooxygenase (COX), the lipoxygenase, and the P-450 epoxygenase pathways. The COX-isoforms-COX-1 and COX-2 are responsible for the conversion of AA to PGH₂, the first step in the generation of TXA₂. Thromboxane synthase (TXA₂S) then catalyzes the conversion of the COX product, PGH₂ to TXA₂

Fig. 2

Structures of TPα and TPβ receptor proteins. The TXA₂ receptor (TP) is a typical G-protein-coupled receptor that is expressed as two different isoforms in humans—TPα and TPβ. TP isoforms share the first 328 amino acids but differ in the length of the C-terminal cytoplasmic tail with TPα shorter than the TPβ isoform (15 versus 79 residues) [24, 25]