ASK1-dependent endothelial cell activation is critical in ovarian cancer growth and metastasis
Mingzhu Yin, Huanjiao Jenny Zhou, Jiqin Zhang, Caixia Lin, Hongmei Li, Xia Li, Yonghao Li, Haifeng Zhang, David G. Breckenridge, Weidong Ji, Wang Min
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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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 5

The SOCS1-ASK1 axis regulates EC permeability and macrophage transmigration by regulating EC junctions.

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The SOCS1-ASK1 axis regulates EC permeability and macrophage transmigrat...
(A–C) Vascular endothelial transgenic mice expressing suppressor of cytokine signaling (VESOCS1) or ASK1 deficiency attenuated macrophage-endothelial transmigration. Isolated WT and VESOCS1 mouse lung microvascular ECs (MLMVEC) were seeded onto the surface of collagen gel in the absence or presence of ID8 cells at the bottom for 12 hours. GFP-expressing macrophages were loaded onto the mouse EC monolayer for 24 hours (A). Transendothelial migrated GFP+ macrophages were visualized by immunofluorescence microscopy. Representative images are shown in B. Magnification, 100×. Quantifications of transmigrated cells are shown in C. Data are expressed as mean ± SEM, n = 10. *P < 0.005, ***P < 0.001 (two-tailed student’s t test. (D–F) Immunostaining of VE-cadherin in MLMVECs isolated from WT, VESOCS1, and ASK1-KO mice. Scale bar: 25 μm. (D and E) Representative images are shown. (F) Quantifications of VE-cadherin immunofluorescence intensity. Data are expressed as mean ± SEM, n = 10. ***P<0.001 (two-sided student’s t test with no correction for multiple comparisons). (G–J) Expression of junctional proteins in WT, ASK1-KO, and VESOSC1 MLMVECs by Western blotting (G and I). Quantitation of blot by densitometry (H and J). Data are expressed as mean ± SEM, n = 3. *P<0.005; **P<0.01; ***P<0.001. Two-sided student’s t test with no correction for multiple comparisons.