Abstract A196: Downregulation of kynurenine 3-monooxygenase (KMO) function prohibits canine mammary gland tumor (cMGT) cells from going wild.

Abstract

Abstract Kynurenine 3-monooxygenase (KMO), mainly found on the outer membrane of the mitochondria, is one of the enzymes in the kynurenine pathway of tryptophan metabolism. KMO catalyzes L-kynurenine (KYN) to form 3-hydroxy kynurenine (3-HK) and further generates the downstream metabolite quinolinic acid (QA) which is an N-methyl-D-aspartate (NMDA) agonist. In the past, KMO was considered to be associated with neurodegenerative diseases because the downstream metabolites demonstrate excitotoxicity to CNS and act as factors in neurodegenerative diseases. In our previous study has shown that overexpression of KMO is related to tumor malignancy and survival time of cMGT-suffering dogs (in progress). In this study, we investigated function of KMO in cMGT cells. First of all, KMO expression of cMGT cells (CMT-1, MPG and CF41.mg) was identified in mRNA and protein level. Second, the application of KMO inhibitor reduced proliferation and migration of cMGT cells. The reduced proliferation, not migration, could be restored by NMDA or QA. Third, the application of KMO inhibitor also decreased the activity of Erk, Akt and STAT3 in cMGT cells. However, the decreased activity of Erk and STAT3 in cMGT cells could be restored through the application of NMDA of QA. Our data suggest that KMO is involved in the proliferation and migration of cMGT cells. Furthermore, the inhibition of proliferation by KMO inhibitor is mainly through Erk and STAT3 signaling cascades and the signaling pathway may be activated through the NMDA receptor. The inhibition of migration by KMO inhibitor is mainly through Akt signaling cascades. In conclusions, KMO might be a new therapeutic target of cMGT due to the downregulation of KMO reduces proliferation and migration of cMGT cells. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A196. Citation Format: Albert T. Liao, Chen-Si Lin, Mei-Hsien Chang. Downregulation of kynurenine 3-monooxygenase (KMO) function prohibits canine mammary gland tumor (cMGT) cells from going wild. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A196.