Abstract
We recently identified 5‐methoxytryptophan (5‐MTP), a novel tryptophan metabolite, as an endogenous inhibitor of cyclooxygenase‐2 (COX‐2) expression. Our reported data show that cancer cells are defective in 5‐MTP production and exogenous 5‐MTP suppresses cancer cell COX‐2 overexpression. Furthermore, 5‐MTP inhibits cancer cell migration and invasion. However, it is unclear whether endogenous 5‐MTP controls cancer cell COX‐2 and COX‐2 mediated cancer growth and metastasis. Since human proliferative fibroblasts (pFb) produce robust 5‐MTP, we determined whether pFb controls cancer cell COX‐2 expression and behavior. pFb co‐cultured with A549 lung cancer cells in a two‐chamber system inhibited PMA‐induced COX‐2 expression and migration in a time‐ and cell number‐dependent manner. pFb blocked A549 epithelial mesenchymal transition (EMT) induced by transforming growth factor‐β (TGFβ). Hydroxyindole O‐methyltransferase (HIOMT) catalyzes the final step of 5‐MTP synthesis. pFb expressed abundant HIOMT proteins. Knockdown of HIOMT in pFb resulted in abrogation of control of A549 COX‐2 expression, migration and EMT in the two‐chamber co‐culture system. These results are consistent with control of A549 COX‐2 expression and EMT/migration by 5‐MTP. We next determined whether 5‐MTP targets p300 histone acetyltransferase (HAT) which is essential for COX‐2 transcriptional activation. Basal p300 HAT activity in A549 was stimulated by proinflammatory cytokines and phorbol esters, which was inhibited by 5‐MTP. 5‐MTP inhibited TGFβ. Co‐cultured with pFb suppressed A549 p300 HAT, TGFβ and COX‐2 which were abrogated by treating pFb with HIOMT siRNA. These findings suggest that fibroblasts control cancer cell COX‐2 expression via inhibition of p300 HAT and TGFβ activation which results in suppression of cancer cell EMT and migration. Fibroblast produced 5‐MTP may confer endogenous resistance to cancer growth and metastasis.
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