| Autor: |
Naixia Zhang, Jun Mi, Aiwu Zhou, Shuhai Lin, Wen Liu, Xianfu Gao, Bo Bi, Jieying Zhang, Yuan Yuan, Youqiong Ye, Wenbin Zeng, Jixi Li, Zhaopeng Shi, Xiang Xu, Guifang Gan, Pengfei Xu |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.21203/rs.3.rs-92311/v1 |
| Popis: |
Kynurenine, a metabolite of tryptophan, promotes immune tolerance in development and tumor evasion by binding to the aryl hydrocarbon receptor (AHR). However, the IDO inhibitors, blocking kynurenine generation, fail in stage III of clinical trials in several tumors for unknown reasons. Here, we report that 3-hydroxyanthranilic acid (3-HAA) synergizes with IDO inhibitors by dramatically increasing the suppression of IDO inhibitors on HCC xenograft growth. The content of 3-HAA, a catabolite of kynurenine, is lower in tumor cells by downregulating its synthetic enzyme KMO/KYNU and/or upregulating its catalytic enzyme HAAO. Overexpression of KMO suppresses tumor formation and tumor growth by increasing endogenous 3-HAA while adding exogenous 3-HAA also inhibits tumor growth. Moreover, we found that 3-HAA directly binds transcription factor YY1 rather than AHR and increasing the PKCζ phosphorylation of YY1 at the Thr 398 in response to 3-HAA; YY1 phosphorylation at T398 increases the YY1 binding to chromatin. 3-HAA-induced Thr398 phosphorylation of YY1 upregulates the expression of dual-specificity phosphatase 6 (DUSP6), etc. DUSP6 overexpression induces apoptosis of hepatocellular carcinoma (HCC) cells and suppresses the HCC growth in vitro and in vivo. The T398 phosphorylation of YY1 is critical for the 3-HAA-induced apoptosis in tumors. These findings demonstrate that kynurenine analog 3-HAA is a functional metabolite associating YY1 as an endogenous ligand, downregulation of 3-HAA is necessary for the rapid growth of tumor cells, suggesting its promising approach in HCC therapy. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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