Prostaglandin-endoperoxide H synthase (PGHS) is a rate-limiting enzyme in the production of prostaglandins (Smith et al., 1996). PGHS catalyzes the cyclooxygenation of arachidonic acid to prostaglandin G2 (PGG2) and the reduction of PGG2 to prostaglandin H2 (PGH2). PGH2 is then metabolized by different synthases to variable function prostanoids, including prostaglandins PGD2, PGE2, PGF2α, and PGI2, and thromboxane (TXA2) (Smith and DeWitt, 1996). PGHS-1 and PGHS-2 are single copy genes that have been mapped to human chromosomes 9 and 1, respectively (Xu et al., 1993; Funk et al., 1991). PGHS-1 is constitutively expressed in most tissues (Smith et al., 2000). In contrast, PGHS-2 is an immediate-early response gene that is highly inducible in nonmalignant cells by cytokines and inflammatory stimuli (Cao et al., 2003; Cao and Smith, 1999; Cao et al., 1998). It is distinct from PGHS-1 with respect to DNA sequence, stability of its mRNA and responses to various stimuli.
In many cancer cell lines and cancer tissues, however, PGHS-2 is constitutively expressed (Davies et al., 2002). The importance of PGHS-2 to tumor cell biology has been attributed in part to the vascular endothelial growth factor (VEGF)-dependent angiogenic activities of PGE2 and PGI2 that support tumor growth (Gately and Li, 2004). Colocalization and interaction of PGHS-2 with caveolin-1, which is segregated from the general prostaglandin synthesis factory in endoplasmic reticulum and nuclear envelope, may contribute to tumorigenesis and to inflammation (Liou et al., 2001). PGE2 can also inhibit apoptosis and immune surveillance (Hoshino et. al., 2003; Ishaque et al., 2003) and PGE2 induces certain DNA repair proteins (Ku70 and Ku80) whose expression may be related to human gastric cancer cell proliferation and carcinogenesis (Lim et al., 2002).
PGHS-2 expression has been associated with less differentiated and more aggressive breast carcinomas and thus may be a useful tissue indicator of prognosis, as well as a target for drug therapy (Wulfing et al., 2004). PGHS-2 overexpression has been reported to occur in more than 40% of human invasive breast cancers and 60% of ductal carcinomas in situ (Wang and Dubois, 2004). Expression of multidrug-resistance gene 1 is increased when PGHS-2 is overexpressed experimentally, suggesting that PGHS-2 contributes to multidrug-resistance in tumors (Patel et al., 2002). In addition, Subbaramaiah et al. (2002) have shown that hyperexpression of PGHS-2 is associated with excessive expression of HER-2/neu in breast cancers through enhancement of the Ras signal.
USPTO Backgrounds
USPTO Backgrounds