Colon Cancer — Understanding How NSAIDs Work
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《新英格兰医药杂志》
Chronic inflammation of the intestine and colorectal cancer are closely associated. The risk of colorectal cancer among patients with ulcerative colitis is an order of magnitude higher than the risk among those without it. Indeed, ulcerative colitis ranks among the top three high-risk conditions for colorectal cancer, together with the syndromes of familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. Although the relationship of the other two conditions to colorectal cancer has a well-understood genetic basis, the association of ulcerative colitis with colorectal cancer is not believed to result from such an underlying predisposition. Rather, the process of chronic inflammation itself appears to underlie the development of intestinal cancer.1
Consistent with this notion is the observation that treatment with nonsteroidal antiinflammatory drugs (NSAIDs) decreases the risk of death from sporadic colorectal cancer. Moreover, NSAID therapy can cause the regression of adenomas in patients with familial adenomatous polyposis.2 NSAIDs target the cyclooxygenase (COX) family, key enzymes in prostaglandin synthesis. These findings are borne out in experiments in animal models: COX inhibitors reduce the risk of adenomas in mice with a mutant adenomatous polyposis coli (apc) gene, the rodent version of familial adenomatous polyposis. The formation of adenomas is also strongly diminished when the apc mutation is bred into mice deficient in COX-1 or COX-2. And a direct effect of prostaglandins on susceptibility to adenomas is indicated by the few adenomas that develop in mice that both have mutant apc and lack the prostaglandin receptor EP2, as compared with the many adenomas that develop in mice with mutant apc alone.3
Despite the very strong evidence of a causative role of inflammatory mediators in intestinal cancer, the underlying molecular mechanisms have remained obscure. A recent study by Castellone and colleagues4 suggests a mechanism by which inflammatory prostaglandins directly impinge on the Wnt pathway, which is targeted by the mutant APC that causes colorectal cancer. The central player in the Wnt pathway is -catenin, and its levels are tightly regulated. In the absence of pathway activation, a complex of proteins, including the tumor suppressors APC, axin, and the serine kinase glycogen synthase kinase 3 (GSK-3), phosphorylates -catenin — marking it for degradation by the proteasome (Figure 1). The extracellular trigger of this pathway is a class of molecules called the Wnt factors; when secreted Wnt molecules engage their receptors on the cell surface, the APC–axin–GSK-3 complex is inhibited. As a result, -catenin is stabilized and enters the nucleus, where it interacts with nuclear transcription factors to drive the transcription of specific target genes that, in turn, drive cell proliferation. Sporadic colorectal cancer is initiated by the mutation-driven activation of the Wnt pathway, typically the loss of the APC tumor-suppressor gene. This event leads to high levels of -catenin in the cytoplasm and nucleus and to inappropriate activation of the target genes. (The increased risk of intestinal neoplasia among patients with familial adenomatous polyposis results from the fact that they already carry one mutant APC allele in their genomes.)
Figure 1. Colorectal Cancer: One Pathway, Two Stimuli.
In Panel A, a mutation in the adenomatous polyposis coli (APC) gene, a susceptibility gene for colon cancer, results in ablation of the APC protein and consequent stabilization of -catenin — the latter accumulates in the cytoplasm, enters the nucleus, and activates genes that stimulate cell proliferation. Wnt signaling, which occurs during normal development, has the same effect, but it does so by down-regulating the complex of proteins that phosphorylates (P) -catenin; phosphorylated -catenin is shunted to the proteasome, where it is degraded. In the presence of APC, the -catenin protein is phosphorylated and then degraded. As shown in Panel B, a recent study by Castellone and colleagues4 suggests that nonsteroidal antiimflammatory drugs (NSAIDs) act through the -catenin pathway to inhibit the progression of colon cancer. NSAIDs inhibit the cyclooxygenases and, hence, the production of prostaglandins (a marker of inflammation). The findings of Castellone et al. suggest that prostaglandin E2, on binding its receptor, activates a cytoplasmic G-protein–coupled receptor (Gs), which in turn binds axin, a component of the complex that phosphorylates -catenin. This event may lead to dissociation of the complex, the accumulation of unphosphorylated -catenin, and ultimately, cell proliferation.
Castellone and colleagues started from the observation that prostaglandin E2 is a potent mitogen for cultured colon-cancer cells and exerts this growth effect through EP2, a G-protein–coupled receptor (Gs). They discovered that prostaglandin E2 strengthened the Wnt signal, already activated to some degree in these cells (owing to the mutant APC gene), and that treatment with prostaglandin E2 enhanced the accumulation of -catenin in the nucleus.
Whence the effect? It is clear that prostaglandin E2 does not activate the dedicated Wnt-receptor complex at the cell surface, and so signaling through the EP2 receptor must somehow enhance downstream signaling events. The experiments of Castellone et al. suggested two routes through which this could happen. The authors noted a motif, called the regulator of G-protein signaling (RGS) domain, in the sequence of the axin protein. In the context of axin, RGS mediates binding with APC, but in such a way that the surface of the G-protein receptor remains available even when bound to APC. Castellone et al. showed that axin interacts with Gs through its RGS domain — which may promote the release of GSK-3 from axin and thus enhance the stability of -catenin. An alternative pathway by which prostaglandin E2 may bump up -catenin levels is by phosphorylation of an inhibitory residue in GSK-3 through a molecule called AKT. This possibility appears to be less likely because this pathway, which is critical to insulin signaling, is thought to be irrelevant to the Wnt cascade.
Castellone et al. have provided evidence that the inflammatory process directly influences the mutationally activated Wnt pathway in colorectal cancer. Although the mechanistic details remain to be addressed, the identification of this connection will aid in the rational use of antiinflammatory therapy in the management of colorectal cancer.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Netherlands Institute for Developmental Biology, Utrecht, the Netherlands.
References
Clevers H. At the crossroads of inflammation and cancer. Cell 2004;118:671-674.
Koehne CH, Dubois RN. COX-2 inhibition and colorectal cancer. Semin Oncol 2004;31:12-21.
Oshima M, Taketo MM. COX selectivity and animal models for colon cancer. Curr Pharm Des 2002;8:1021-1034.
Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 2005;310:1504-1510.(Hans Clevers, M.D., Ph.D.)
Consistent with this notion is the observation that treatment with nonsteroidal antiinflammatory drugs (NSAIDs) decreases the risk of death from sporadic colorectal cancer. Moreover, NSAID therapy can cause the regression of adenomas in patients with familial adenomatous polyposis.2 NSAIDs target the cyclooxygenase (COX) family, key enzymes in prostaglandin synthesis. These findings are borne out in experiments in animal models: COX inhibitors reduce the risk of adenomas in mice with a mutant adenomatous polyposis coli (apc) gene, the rodent version of familial adenomatous polyposis. The formation of adenomas is also strongly diminished when the apc mutation is bred into mice deficient in COX-1 or COX-2. And a direct effect of prostaglandins on susceptibility to adenomas is indicated by the few adenomas that develop in mice that both have mutant apc and lack the prostaglandin receptor EP2, as compared with the many adenomas that develop in mice with mutant apc alone.3
Despite the very strong evidence of a causative role of inflammatory mediators in intestinal cancer, the underlying molecular mechanisms have remained obscure. A recent study by Castellone and colleagues4 suggests a mechanism by which inflammatory prostaglandins directly impinge on the Wnt pathway, which is targeted by the mutant APC that causes colorectal cancer. The central player in the Wnt pathway is -catenin, and its levels are tightly regulated. In the absence of pathway activation, a complex of proteins, including the tumor suppressors APC, axin, and the serine kinase glycogen synthase kinase 3 (GSK-3), phosphorylates -catenin — marking it for degradation by the proteasome (Figure 1). The extracellular trigger of this pathway is a class of molecules called the Wnt factors; when secreted Wnt molecules engage their receptors on the cell surface, the APC–axin–GSK-3 complex is inhibited. As a result, -catenin is stabilized and enters the nucleus, where it interacts with nuclear transcription factors to drive the transcription of specific target genes that, in turn, drive cell proliferation. Sporadic colorectal cancer is initiated by the mutation-driven activation of the Wnt pathway, typically the loss of the APC tumor-suppressor gene. This event leads to high levels of -catenin in the cytoplasm and nucleus and to inappropriate activation of the target genes. (The increased risk of intestinal neoplasia among patients with familial adenomatous polyposis results from the fact that they already carry one mutant APC allele in their genomes.)
Figure 1. Colorectal Cancer: One Pathway, Two Stimuli.
In Panel A, a mutation in the adenomatous polyposis coli (APC) gene, a susceptibility gene for colon cancer, results in ablation of the APC protein and consequent stabilization of -catenin — the latter accumulates in the cytoplasm, enters the nucleus, and activates genes that stimulate cell proliferation. Wnt signaling, which occurs during normal development, has the same effect, but it does so by down-regulating the complex of proteins that phosphorylates (P) -catenin; phosphorylated -catenin is shunted to the proteasome, where it is degraded. In the presence of APC, the -catenin protein is phosphorylated and then degraded. As shown in Panel B, a recent study by Castellone and colleagues4 suggests that nonsteroidal antiimflammatory drugs (NSAIDs) act through the -catenin pathway to inhibit the progression of colon cancer. NSAIDs inhibit the cyclooxygenases and, hence, the production of prostaglandins (a marker of inflammation). The findings of Castellone et al. suggest that prostaglandin E2, on binding its receptor, activates a cytoplasmic G-protein–coupled receptor (Gs), which in turn binds axin, a component of the complex that phosphorylates -catenin. This event may lead to dissociation of the complex, the accumulation of unphosphorylated -catenin, and ultimately, cell proliferation.
Castellone and colleagues started from the observation that prostaglandin E2 is a potent mitogen for cultured colon-cancer cells and exerts this growth effect through EP2, a G-protein–coupled receptor (Gs). They discovered that prostaglandin E2 strengthened the Wnt signal, already activated to some degree in these cells (owing to the mutant APC gene), and that treatment with prostaglandin E2 enhanced the accumulation of -catenin in the nucleus.
Whence the effect? It is clear that prostaglandin E2 does not activate the dedicated Wnt-receptor complex at the cell surface, and so signaling through the EP2 receptor must somehow enhance downstream signaling events. The experiments of Castellone et al. suggested two routes through which this could happen. The authors noted a motif, called the regulator of G-protein signaling (RGS) domain, in the sequence of the axin protein. In the context of axin, RGS mediates binding with APC, but in such a way that the surface of the G-protein receptor remains available even when bound to APC. Castellone et al. showed that axin interacts with Gs through its RGS domain — which may promote the release of GSK-3 from axin and thus enhance the stability of -catenin. An alternative pathway by which prostaglandin E2 may bump up -catenin levels is by phosphorylation of an inhibitory residue in GSK-3 through a molecule called AKT. This possibility appears to be less likely because this pathway, which is critical to insulin signaling, is thought to be irrelevant to the Wnt cascade.
Castellone et al. have provided evidence that the inflammatory process directly influences the mutationally activated Wnt pathway in colorectal cancer. Although the mechanistic details remain to be addressed, the identification of this connection will aid in the rational use of antiinflammatory therapy in the management of colorectal cancer.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Netherlands Institute for Developmental Biology, Utrecht, the Netherlands.
References
Clevers H. At the crossroads of inflammation and cancer. Cell 2004;118:671-674.
Koehne CH, Dubois RN. COX-2 inhibition and colorectal cancer. Semin Oncol 2004;31:12-21.
Oshima M, Taketo MM. COX selectivity and animal models for colon cancer. Curr Pharm Des 2002;8:1021-1034.
Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 2005;310:1504-1510.(Hans Clevers, M.D., Ph.D.)