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

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

doi:10.1172/jci.insight.91828

Cited by 33 publications

(23 citation statements)

References 58 publications

(67 reference statements)

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“…This suggest that other cell types such as myocyte rather than EC primarily contributes to VEGF-A expression in ischemic hindlimb. SENP1-mediated ASK1 activation (p-ASK1), which is known to mediate inflammation and cellular apoptosis 30 , 31 , was not significantly attenuated by SENP1 deletion in ischemic muscle. These data suggest that ASK1 signaling did not contribute to reduced macrophage infiltration (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis

Zhou

Wang

et al. 2018

Nat Commun

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Regulation of VEGFR2 represents an important mechanism for the control of angiogenesis. VEGFR2 activity can be regulated by post-translational modifications such as ubiquitination and acetylation. However, whether VEGFR2 can be regulated by SUMOylation has not been investigated. Here we show that endothelial-specific deletion of the SUMO endopeptidase SENP1 reduces pathological angiogenesis and tissue repair during hindlimb ischemia, and VEGF-induced angiogenesis in the cornea, retina, and ear. SENP1-deficient endothelial cells show increased SUMOylation of VEGFR2 and impaired VEGFR2 signalling. SUMOylation at lysine 1270 retains VEGFR2 in the Golgi and reduces its surface expression, attenuating VEGFR2-dependent signalling. Moreover, we find that SENP1 is downregulated and VEGFR2 hyper-SUMOylated in diabetic settings and that expression of a non-SUMOylated form of VEGFR2 rescues angiogenic defects in diabetic mice. These results show that VEGFR2 is regulated by deSUMOylation during pathological angiogenesis, and propose SENP1 as a potential therapeutic target for the treatment of diabetes-associated angiogenesis.

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Section: Resultsmentioning

confidence: 99%

SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis

Zhou

Wang

et al. 2018

Nat Commun

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“…To further understand the mechanisms by which BRD4 inhibition affected tumor growth, we examined the effects of NHWD-870 treatment on tumor microenvironment. As we recently reported that in ovarian cancer, TAMs form spheroid with ovarian cancer cells, facilitate their implantation, and promote tumor cell proliferation and transcoelomic metastasis 28,29 , we focused our efforts on TAMs. We observed that the numbers of TAMs (CD68 + cells) were significantly lower in subcutaneous tumors formed by either H526 SCLC or A2780 OC cells after NHWD-870 treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It was proposed that TAMs are polarized in the tumor microenvironment toward an M2-like subtype during tumor progression, and this change underlies their ability to promote tumor growth and angiogenesis 27 . We recently reported that TAMs in peritoneal cavity promote ovarian cancer (OC) cell survival, proliferation, and early transcoelomic metastasis by facilitating TAM-OC cell spheroid formation 28,29 . In addition to their direct effects on tumor cells, TAMs suppress anti-tumor immunity by preventing activation of dendritic cells, cytotoxic T lymphocytes, and natural killer cells 25 .…”

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confidence: 99%

Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction

et al. 2020

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Small molecule inhibitor of the bromodomain and extraterminal domain (BET) family proteins is a promising option for cancer treatment. However, current BET inhibitors are limited by their potency or oral bioavailability. Here we report the discovery and characterization of NHWD-870, a BET inhibitor that is more potent than three major clinical stage BET inhibitors BMS-986158, OTX-015, and GSK-525762. NHWD-870 causes tumor shrinkage or significantly suppresses tumor growth in nine xenograft or syngeneic models. In addition to its ability to downregulate c-MYC and directly inhibit tumor cell proliferation, NHWD-870 blocks the proliferation of tumor associated macrophages (TAMs) through multiple mechanisms, partly by reducing the expression and secretion of macrophage colonystimulating factor CSF1 by tumor cells. NHWD-870 inhibits CSF1 expression through suppressing BRD4 and its target HIF1α. Taken together, these results reveal a mechanism by which BRD4 inhibition suppresses tumor growth, and support further development of NHWD-870 to treat solid tumors.

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“…After applying HRP substrate, 3.3′-diaminobenzidine tetrahydrochloride (D3939–1set, Sigma) in 0.01% H 2 O 2, for 2–10 minutes, the slides were counterstained with Meyer’s hematoxylin for 30 to 60 s and mounted with mounting medium for visualization under microscope. ( Yin et al, 2016 ; Yin et al, 2017 ). Scoring of SUMO1 and ERα in EC samples via IHC staining follows the methods previously published.…”

Section: Methodsmentioning

confidence: 99%

CD34+KLF4+ Stromal Stem Cells Contribute to Endometrial Regeneration and Repair

et al. 2019

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SUMMARY The regenerative capacity of the human endometrium requires a population of local stem cells. However, the phenotypes, locations, and origin of these cells are still unknown. In a mouse menstruation model, uterine stromal SM22α + -derived CD34 + KLF4 + stem cells are activated and integrate into the regeneration area, where they differentiate and incorporate into the endometrial epithelium; this process is correlated with enhanced protein SUMOylation in CD34 + KLF4 + cells. Mice with a stromal SM22α-specific SENP1 deletion (SENP1smKO) exhibit accelerated endometrial repair in the regeneration model and develop spontaneous uterine hyperplasia. Mechanistic studies suggest that SENP1 deletion induces SUMOylation of ERα, which augments ERα transcriptional activity and proliferative signaling in SM22α + CD34 + KLF4 + cells. These cells then transdifferentiate to the endometrial epithelium. Our study reveals that CD34 + KLF4 + stromal-resident stem cells directly contribute to endometrial regeneration, which is regulated through SENP1-mediated ERα suppression.

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

Cited by 33 publications

References 58 publications

SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis

SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis

Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction

CD34+KLF4+ Stromal Stem Cells Contribute to Endometrial Regeneration and Repair

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