The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2

Ash, Dipankar; Varadarajan, Sudhahar; Youn, Seock Won; Okur, Mustafa Nazir; Das, Archita; O’Bryan, John P.; McMenamin, Maggie; Hou, Yali; Kaplan, Jack H.; Fukai, Tohru; Ushio‐Fukai, Masuko

doi:10.1038/s41467-021-23408-1

Cited by 62 publications

(41 citation statements)

References 79 publications

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“…However, our data ruled out defects in VEGFR2 transcription. As for VEGFR2 degradation, this process depends on autophagy, the inhibition of which can increase VEGFR2 levels and angiogenesis [ 22 ]. While we confirmed that Dox increased autophagic flux [ 23 ], inhibition of autophagy or of the proteasome did not restore VEGFR2 levels in Dox-treated HUVECs.…”

Section: Discussionmentioning

confidence: 99%

Transient Exposure of Endothelial Cells to Doxorubicin Leads to Long-Lasting Vascular Endothelial Growth Factor Receptor 2 Downregulation

Graziani

Scorrano

Pontarin

2022

Cells

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Doxorubicin (Dox) is an effective antineoplastic drug with serious cardiotoxic side effects that persist after drug withdrawal and can lead to heart failure. Dysregulation of vascular endothelium has been linked to the development of Dox-induced cardiotoxicity, but it is unclear whether and how transient exposure to Dox leads to long-term downregulation of Endothelial Vascular Endothelial Growth Factor Receptor type2 (VEGFR2), essential for endothelial cells function. Using an in vitro model devised to study the long-lasting effects of brief endothelial cells exposure to Dox, we show that Dox leads to sustained protein synthesis inhibition and VEGFR2 downregulation. Transient Dox treatment led to the development of long-term senescence associated with a reduction in VEGFR2 levels that persisted days after drug withdrawal. By analyzing VEGFR2 turnover, we ruled out that its downregulation was depended on Dox-induced autophagy. Conversely, Dox induced p53 expression, reduced mTOR-dependent translation, and inhibited global protein synthesis. Our data contribute to a mechanistic basis to the permanent damage caused to endothelial cells by short-term Dox treatment.

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Section: Discussionmentioning

confidence: 99%

Transient Exposure of Endothelial Cells to Doxorubicin Leads to Long-Lasting Vascular Endothelial Growth Factor Receptor 2 Downregulation

Graziani

Scorrano

Pontarin

2022

Cells

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“…PLVAP+ ECs were also identified in different peripheral clusters, suggesting that they originally formed an intermediate subpopulation that migrated into the tumor core. Moreover, the tumoral ECs’ cluster expresses VEGFR2, a molecule that facilitates the communication of blood vessels with tumor hepatocytes, promoting angiogenesis [ 141 ]. A comparative study of TAEs with LSECs demonstrated phenotypic differences related to angiogenesis modulation.…”

Section: Tumor Microenvironment In Hcc: the Importance Of The Nichementioning

confidence: 99%

Cell Death in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Opportunities

García-Pras

Fernández‐Iglesias

Gracia‐Sancho

et al. 2021

Cancers

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Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the third leading cause of cancer death worldwide. Closely associated with liver inflammation and fibrosis, hepatocyte cell death is a common trigger for acute and chronic liver disease arising from different etiologies, including viral hepatitis, alcohol abuse, and fatty liver. In this review, we discuss the contribution of different types of cell death, including apoptosis, necroptosis, pyroptosis, or autophagy, to the progression of liver disease and the development of HCC. Interestingly, inflammasomes have recently emerged as pivotal innate sensors with a highly pathogenic role in various liver diseases. In this regard, an increased inflammatory response would act as a key element promoting a pro-oncogenic microenvironment that may result not only in tumor growth, but also in the formation of a premetastatic niche. Importantly, nonparenchymal hepatic cells, such as liver sinusoidal endothelial cells, hepatic stellate cells, and hepatic macrophages, play an important role in establishing the tumor microenvironment, stimulating tumorigenesis by paracrine communication through cytokines and/or angiocrine factors. Finally, we update the potential therapeutic options to inhibit tumorigenesis, and we propose different mechanisms to consider in the tumor microenvironment field for HCC resolution.

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“…Increasing evidence has unraveled that angiogenesis is crucial for tumour progression and is highly dependent on VEGF expressed by most malignant tumours [25][26][27] . Additionally, FRS2-mediated signals were validated to promote tumour angiogenesis and predict poor prognosis in prostate carcinoma, high-grade serous ovarian cancer and liposarcoma [28][29][30] .…”

Section: Discussionmentioning

confidence: 99%

A novel risk score model based on five angiogenesis-related long non-coding RNAs for bladder urothelial carcinoma

Zhang

Xiang

et al. 2022

Preprint

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Background Tumour angiogenesis is an independent risk factor for bladder urothelial carcinoma (BUC) progression, but viable and promising antiangiogenic targets are understudied. Long non-coding RNAs (lncRNAs) have been reported to play significant roles in angiogenesis. Methods The clinical data of BUC patients were obtained from TCGA database and clinical specimens of 138 BUC patients. Angiogenesis-related long non-coding RNAs (ARLNRs) were extracted from The Molecular Signatures Database v4.0. Univariate and multivariate COX regression analyses were used to further identify survival-related ARLNRs (sARLNRs). A chain of techniques (FACS, western blotting, qPCR, immunohistochemistry, tube formation, migration and invasion assays) and co-culture models were utilized to validate the clinical significances and angiogenetic correlation of sARLNRs. Results Five sARLNRs were employed to establish angiogenesis-related risk score model, by which the patients in the low-risk group obtained longer overall survival than those in the high-risk group. Two sARLNRa in the risk score model (AC005625.1 and AC008760.1) expressed lower in BUC cell lines and tumour tissues than that in normal urothelial cells and adjacent normal tissues, with further lower expression in more advanced T stages. More importantly, the expression of AC005625.1 and AC008760.1 expression was negatively related to endothelial cells (ECs) percentage, tumour size and muscle invasion status. A prominently higher proportion of ECs was detected in tumour tissues with lower expression of AC005625.1 and AC008760.1. Furthermore, in the co-culture model of T24 cells and HUVEC cells, knockdown of AC005625.1 and AC008760.1 in BUC cells increased tube formation, migration and invasion abilities of HUVEC cells. The expression levels of CD31, VEGF-A, VIMENTIN and N-CADHERIN were also enhanced in HUVEC cells co-cultured with siR-AC005625.1 and siR-AC008760.1-treated T24 cells. Conclusion In the study, we identify five sARLNRs and validate their clinical significances, angiogenesis correlation and prognosis-predictive values in BUC. These results may provide a new perspective and some promising antiangiogenic targets for clinical diagnosis and treatment strategies of BUC.

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The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2

Cited by 62 publications

References 79 publications

Transient Exposure of Endothelial Cells to Doxorubicin Leads to Long-Lasting Vascular Endothelial Growth Factor Receptor 2 Downregulation

Transient Exposure of Endothelial Cells to Doxorubicin Leads to Long-Lasting Vascular Endothelial Growth Factor Receptor 2 Downregulation

Cell Death in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Opportunities

A novel risk score model based on five angiogenesis-related long non-coding RNAs for bladder urothelial carcinoma

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