TY - JOUR
T1 - 1-L-MT, an IDO inhibitor, prevented colitis-associated cancer by inducing CDC20 inhibition-mediated mitotic death of colon cancer cells
AU - Liu, Xiuting
AU - Zhou, Wei
AU - Zhang, Xin
AU - Ding, Yang
AU - Du, Qianming
AU - Hu, Rong
N1 - Publisher Copyright:
© 2018 UICC
PY - 2018/9/15
Y1 - 2018/9/15
N2 - Indoleamine 2,3-dioxygenase 1 (IDO1), known as IDO, catabolizes tryptophan through kynurenine pathway, whose activity is correlated with impaired clinical outcome of colorectal cancer. Here we showed that 1-L-MT, a canonical IDO inhibitor, suppressed proliferation of human colorectal cancer cells through inducing mitotic death. Our results showed that inhibition of IDO decreased the transcription of CDC20, which resulted in G2/M cycle arrest of HCT-116 and HT-29. Furthermore, 1-L-MT induced mitochondria injuries and caused apoptotic cancer cells. Importantly, 1-L-MT protected mice from azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon carcinogenesis, with reduced mortality, tumor number and size. What is more, IDO1–/– mice exhibited fewer tumor burdens and reduced proliferation in the neoplastic epithelium, while, 1-L-MT did not exhibit any further protective effects on IDO–/– mice, confirming the critical role of IDO and the protective effect of 1-L-MT-mediated IDO inhibition in CRC. Furthermore, 1-L-MT also alleviated CRC in Rag1–/– mice, demonstrating the modulatory effects of IDO independent of its role in modulating adaptive immunity. Taken together, our findings validated that the anti-proliferation effect of 1-L-MT in vitro and the prevention of CRC in vivo were through IDO-induced cell cycle disaster of colon cancer cells. Our results identified 1-L-MT as a promising candidate for the chemoprevention of CRC.
AB - Indoleamine 2,3-dioxygenase 1 (IDO1), known as IDO, catabolizes tryptophan through kynurenine pathway, whose activity is correlated with impaired clinical outcome of colorectal cancer. Here we showed that 1-L-MT, a canonical IDO inhibitor, suppressed proliferation of human colorectal cancer cells through inducing mitotic death. Our results showed that inhibition of IDO decreased the transcription of CDC20, which resulted in G2/M cycle arrest of HCT-116 and HT-29. Furthermore, 1-L-MT induced mitochondria injuries and caused apoptotic cancer cells. Importantly, 1-L-MT protected mice from azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon carcinogenesis, with reduced mortality, tumor number and size. What is more, IDO1–/– mice exhibited fewer tumor burdens and reduced proliferation in the neoplastic epithelium, while, 1-L-MT did not exhibit any further protective effects on IDO–/– mice, confirming the critical role of IDO and the protective effect of 1-L-MT-mediated IDO inhibition in CRC. Furthermore, 1-L-MT also alleviated CRC in Rag1–/– mice, demonstrating the modulatory effects of IDO independent of its role in modulating adaptive immunity. Taken together, our findings validated that the anti-proliferation effect of 1-L-MT in vitro and the prevention of CRC in vivo were through IDO-induced cell cycle disaster of colon cancer cells. Our results identified 1-L-MT as a promising candidate for the chemoprevention of CRC.
KW - CDC20
KW - IDO
KW - Kyn
KW - colorectal cancer
UR - http://www.scopus.com/inward/record.url?scp=85046553652&partnerID=8YFLogxK
U2 - 10.1002/ijc.31417
DO - 10.1002/ijc.31417
M3 - Article
C2 - 29607498
AN - SCOPUS:85046553652
SN - 0020-7136
VL - 143
SP - 1516
EP - 1529
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 6
ER -