ASK1-dependent endothelial cell activation is critical in ovarian cancer growth and metastasis
Mingzhu Yin, … , Weidong Ji, Wang Min
Mingzhu Yin, … , Weidong Ji, Wang Min
Published September 21, 2017
Citation Information: JCI Insight. 2017;2(18):e91828. https://doi.org/10.1172/jci.insight.91828.
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Research Article Oncology Therapeutics

ASK1-dependent endothelial cell activation is critical in ovarian cancer growth and metastasis

Abstract

We have recently reported that tumor-associated macrophages (TAMs) promote early transcoelomic metastasis of ovarian cancer by facilitating TAM–ovarian cancer cell spheroid formation. ASK1 is known to be important for macrophage activation and inflammation-mediated tumorigenesis. In the present study, we show that ASK1 deficiency attenuates TAM-spheroid formation and ovarian cancer progression in an orthotopic ovarian cancer model. Interestingly, ASK1 in stroma, but not in TAMs, is critical for peritoneal tumor growth of ovarian cancer. Moreover, overexpression of an ASK1 inhibitory protein (suppressor of cytokine signaling-1; SOCS1) in vascular endothelium attenuates vascular permeability, TAM infiltration, and ovarian cancer growth. Mechanistically, we show that ASK1 mediates degradation of endothelial junction protein VE-cadherin via a lysosomal pathway to promote macrophage transmigration. Importantly, a pharmacological ASK1 inhibitor prevents tumor-induced vascular leakage, macrophage infiltration, and tumor growth in two mouse models. Since transcoelomic metastasis is also associated with many other cancers, such as pancreatic and colon cancers, our study provides ASK1 as a therapeutic target for the treatment of ovarian cancer and other transcoelomic metastasis cancers.

Authors

Mingzhu Yin, Huanjiao Jenny Zhou, Jiqin Zhang, Caixia Lin, Hongmei Li, Xia Li, Yonghao Li, Haifeng Zhang, David G. Breckenridge, Weidong Ji, Wang Min

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Figure 6

ASK1 mediates VE-cadherin degradation via a lysosomal pathway.

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ASK1 mediates VE-cadherin degradation via a lysosomal pathway. Human lun...
Human lung microvessel ECs (HLMVEC) were untreated or treated with TNF (10 ng/ml for 30 min) in the absence or presence of various inhibitors of ASK1, JNK, p38, MG132, and chloroquin as indicated. (A) Coimmunofluorescent staining of VE-cadherin (red) and late endosome marker Lamp1 (green). Representative images are shown. Scale bars: 10 μm. (B) Quantifications of junctional VE-cadherin. Data are expressed as mean ± SEM, n = 30 (10 images from each experiment). ***P<0.001. (C and D) VE-cadherin protein levels were determined by Western blotting (C). Relative VE-cadherin levels were quantified by densitometry with normalization of untreated group (D). (E and F) HLMVEC were untreated or treated with TNF (10 ng/ml for 30 min) in the absence or presence of various concentrations of ASK1. VE-cadherin and p–VE-cadherin protein levels were determined by Western blotting (E). Relative VE-cadherin and p–VE-cadherin levels were quantified by densitometry with normalization of untreated group (F). Data are expressed as mean ± SEM, n = 3. **P < 0.01 (two-sided student’s t test with no correction for multiple comparisons). (G) Schematics of ASK1-JNK–mediated VE-cadherin lysosomal-dependent degradation in ECs. TNF-α activates ASK1-JNK signaling and enhances phosphorylation and degradation of VE-cadherin through the lysosomal pathway in ECs. Inhibition of ASK1 (GS444217), JNK (SP600125), and lysosome (chloroquine) prevents VE-cadherin phosphorylation and degradation.