Abstract:
:Cyclooxygenase-2 (COX-2) expression is induced by mitogenic and proinflammatory factors. Its overexpression plays a causal role in inflammation and tumorigenesis. COX-2 expression is tightly regulated, but the mechanisms are largely unclear. Here we show the control of COX-2 expression by an endogenous tryptophan metabolite, 5-methoxytryptophan (5-MTP). By using comparative metabolomic analysis and enzyme-immunoassay, our results reveal that normal fibroblasts produce and release 5-MTP into the extracellular milieu whereas A549 and other cancer cells were defective in 5-MTP production. 5-MTP was synthesized from L-tryptophan via tryptophan hydroxylase-1 and hydroxyindole O-methyltransferase. 5-MTP blocked cancer cell COX-2 overexpression and suppressed A549 migration and invasion. Furthermore, i.p. infusion of 5-MTP reduced tumor growth and cancer metastasis in a murine xenograft tumor model. We conclude that 5-MTP synthesis represents a mechanism for endogenous control of COX-2 overexpression and is a valuable lead for new anti-cancer and anti-inflammatory drug development.
journal_name
Proc Natl Acad Sci U S Aauthors
Cheng HH,Kuo CC,Yan JL,Chen HL,Lin WC,Wang KH,Tsai KK,Guvén H,Flaberg E,Szekely L,Klein G,Wu KKdoi
10.1073/pnas.1209919109subject
Has Abstractpub_date
2012-08-14 00:00:00pages
13231-6issue
33eissn
0027-8424issn
1091-6490pii
1209919109journal_volume
109pub_type
杂志文章abstract::Whether and how human populations exposed to the agricultural revolution are still affected by Darwinian selection remains controversial among social scientists, biologists, and the general public. Although methods of studying selection in natural populations are well established, our understanding of selection in hum...
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