Anti-cancer Effects of MW-03, a Novel Indole Compound, by Inducing 15-Hydroxyprostaglandin Dehydrogenase and Cellular Growth Inhibition in the LS174T Human Colon Cancer Cell Line

Abstract

Increases in the expression of prostaglandin E 2 (PGE 2 ) are widely known to be involved in aberrant growth in the early stage of colon cancer development. We herein demonstrated that the novel indole compound MW-03 reduced PGE 2 -induced cAMP formation by catalization to an inactive metabolite by inducing 15-hydroxyprostaglandin dehydrogenase through the activation of peroxisome proliferator-activated receptor-γ. MW-03 also inhibited colon cancer cell growth by arresting the cell cycle at the S phase. Although the target of MW-03 for cell cycle inhibition has not yet been identified, these dual anti-cancer effects of MW-03 itself and/or its leading compound(s) on colon cancer cells may reduce colon cancer development and, thus, have potential as a novel treatment for the early stage of this disease.Key words indole compound; MW-03; prostaglandin E 2 ; 15-hydroxyprostaglandin dehydrogenase; peroxisome proliferator-activated receptor-γ; colon cancer One major prostanoid, prostaglandin E 2 (PGE 2 ) is widely known to be up-regulated by the action of increased levels of cyclooxygenase-2 (COX-2) in colorectal cancer.1,2) Thus, the enhanced expression of COX-2 and biosynthesis of PGE 2 are responsible for the malignancy of diseases.1,2) Since the overexpression of COX-2 and PGE 2 is frequently observed in the early stage of colorectal cancer development, they are considered to be the biomarkers of this stage. 3)Cruciferous vegetables, such as cauliflower, cabbage, and broccoli, are regarded as good food sources for reducing the risk of cancer including colon cancer. 4,5) Natural compounds that contain indole structures are relatively rich in cruciferous vegetables. 4,5) The consumption of cruciferous vegetables has been recommended by the National Research Council in the United States because of the protective mechanisms of phytochemicals including derivatives of indoles, e.g. indole-3-carbinol and diindolylmethane.4,5) These indole derivatives have been shown to induce cancer cell death such as apoptosis; although many mechanisms are suggested and reported, 4,5) the exact mechanisms underlying currently remain unclear. These cell death mechanisms are not only exerted by phytochemical indoles, but also by synthesized indoles such as one popular non-steroidal anti-inflammatory drug (NSAID), indomethacin. 6,7)Some indole compounds have been used as tools for researching prostanoid receptors and/or their signaling pathways. Among them, indomethacin has been used as an E-type prostanoid 2 (EP2) prostanoid receptor antagonist, 8) D-type prostanoid receptor antagonist, 9,10) chemoattractant receptorhomologous molecule expressed on T helper 2 cell receptor agonist, 11) and peroxisome proliferator-activated receptor-γ (PPARγ) agonist/antagonist, 12,13) by itself and/or its leading compounds with cyclooxygenase inhibition-independent activities.14) A previous study reported that indomethacin induced 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that catalyzes prostanoids such as PGE 2 to inactive, the metabolite...

Tumour suppressor 15-hydroxyprostaglandin dehydrogenase induces differentiation in colon cancer via GLI1 inhibition

“…The PGE 2 -degrading enzyme 15-PGDH has been recently studied to determine its antitumour potential in solid tumours such as pancreas and lung cancer 33,34 in addition to colon cancer 19,20,35 . Some studies have focused on the antitumour role of 15-PGDH through PGE 2 degradation 36,37 , whereas the findings of other studies have implied a differentiation-promoting role 20 .…”