STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells
Yuying Liu, … , F. Xiao-Feng Qin, Bo Huang
Yuying Liu, … , F. Xiao-Feng Qin, Bo Huang
Published February 12, 2018
Citation Information: J Clin Invest. 2018;128(3):1057-1073. https://doi.org/10.1172/JCI96329.
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Research Article Immunology

STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells

Abstract

Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell–intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-β treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27–dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models. Specifically, blocking AhR redirected IFN-β signaling to STAT3 phosphorylation through both tyrosine and serine sites, which subsequently facilitated STAT3 nuclear translocation and subsequent binding to the p53 promoter in the nucleus. Upregulation of p53 in turn disrupted the pentose phosphate pathway, leading to excessive ROS production and dormant TRC death. Additionally, in melanoma patients, high expression of IFN-β correlated with tumor cell dormancy. Identification of this mechanism for controlling TRC dormancy by IFN-β provides deeper insights into cancer-immune interaction and potential new cancer immunotherapeutic modalities.

Authors

Yuying Liu, Jiadi Lv, Jinyan Liu, Xiaoyu Liang, Xun Jin, Jing Xie, Le Zhang, Degao Chen, Roland Fiskesund, Ke Tang, Jingwei Ma, Huafeng Zhang, Wenqian Dong, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Qingzhu Jia, Bo Zhu, Yan Kong, Jun Guo, Haizeng Zhang, Zhuo-Wei Hu, Xuetao Cao, F. Xiao-Feng Qin, Bo Huang

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Figure 3

IFN-β mobilizes IDO1/AhR/p27 pathway to mediate TRC dormancy.

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IFN-β mobilizes IDO1/AhR/p27 pathway to mediate TRC dormancy. (A) B16 TR...
(A) B16 TRCs or A375 TRCs were treated with IFN-β for 24 hours. IDO1 expression was determined by Western blot. (B) B16 or A375 cells, cultured on rigid plastic or in soft 3D fibrin gels, were treated with 5 ng/ml IFN-β for 2 days. Kyn levels in cell lysate were determined. (C) IFN-β enhanced luciferase activity. B16 TRCs or A375 TRCs were transiently transfected with a luciferase reporter plasmid of pGL3/CYP1A1 promoter with or without Flag-AhR in the presence or absence of IFN-β for 24 hours. (D) Both IFN-β and Kyn promoted the translocation of AhR from the cytosol to the nucleus by immunostaining assay. Scale bar: 10 μm. (E) Cell fraction of cytosol (Cyt) and nucleus (Nuc) was analyzed by Western blot. (F) Expression of p27 in TRCs or differentiated control (Con) cells with or without IFN-β treatment. (G) B16 or A375 TRCs were transfected with a luciferase reporter plasmid of pGL3/p27 promoter with or without Flag-AhR in the presence or absence of IFN-β for 24 hours. (H) Single guide GFP (SGGFP) or p27-sgRNA-TRCs were treated with IFN-β (5 ng/ml) for 2 to 4 days. The colony size is presented. SG1, p27-sgRNA-SG1; SG2, p27-sgRNA-SG2. Scale bars: 50 μm. Data are from 3 independent experiments and represent mean ± SEM. **P < 0.01, by 2-tailed Student’s t test (B, C, and H) and 1-way ANOVA (D and G).