Cysteine oxidation of copper transporter CTR1 drives VEGFR2 signalling and angiogenesis

Das, Archita; Ash, Dipankar; Fouda, Abdelrahman Y.; Varadarajan, Sudhahar; Kim, Young-Mee; Hou, Yali; Hudson, Farlyn Z.; Stansfield, Brian K.; Caldwell, Ruth B.; McMenamin, Malgorzata; Littlejohn, Rodney; Su, Huabo; Regan, Meredith M.; Merrill, Bradley J.; Poole, Leslie B.; Kaplan, Jack H.; Fukai, Tohru; Ushio‐Fukai, Masuko

doi:10.1038/s41556-021-00822-7

Cited by 102 publications

(75 citation statements)

References 62 publications

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“…Similar to our finding, some studies have highlighted that SP1 and p53 often cooperate to regulate many tumor-related signaling pathways ( 41 ). In addition to transport copper and platinum, a recent study shows that CTR1 is rapidly sulfenylated at Cys189 at its cytosolic C terminus after stimulation with vascular endothelial growth factor (VEGF), which induces CTR1-vascular endothelial growth factor receptor type 2(VEGFR2) disulfide bond formation and their co-internalization to early endosomes, driving sustained VEGFR2 signaling to enhance angiogenesis ( 42 ). It is needed to explore further whether cytokines, like VEGF, have a possible function in the process of CTR1-mediated cisplatin absorption.…”

Section: Discussionmentioning

confidence: 99%

p53 inhibits CTR1-mediated cisplatin absorption by suppressing SP1 nuclear translocation in osteosarcoma

et al. 2023

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BackgroundOsteosarcoma (OS) is a malignant bone tumor mainly affecting children and young adolescents. Cisplatin is a first-line chemotherapy drug for OS, however, drug resistance severely limits the survival of OS. Nevertheless, cellular factors in cisplatin resistance for OS remain obscure. In this study, the function and potential mechanism of p53 in cisplatin absorption were explored in OS cells.MethodsThe CRISPR-Cas9 gene editing technology was performed to obtain p53 gene knock-out U2OS cells. The p53 over-expression 143B cell line was established by lentivirus-mediated virus infection. Moreover, the functions of p53 and CTR1 in cisplatin absorption were assessed by inductively coupled plasma mass spectrometry (ICP-MS) through CTR1 over-expression and knock-down. Further, the DNA binding activity of SP1 on CTR1 gene promoter was determined by dual-luciferase assay and chromatin immunoprecipitation (ChIP) assay. The functional regulation of p53 on SP1 was studied by nucleocytoplasmic separation assay and electrophoretic mobility shift assay (EMSA). The interaction between p53 and SP1 was verified by Co-Immunoprecipitation assay.ResultsUnder cisplatin treatment, p53 knock-out promoted CTR1 expression and cisplatin uptake, while p53 overexpression inhibited CTR1 expression and cisplatin uptake. Moreover, p53 regulated CTR1 level not by binding to CTR1 promoter directly but by suppressing the nuclear translocation of transcription factor specificity protein 1 (SP1). It was verified that SP1 is directly bound with CTR1 promoter. SP1 overexpression stimulated CTR1 expression, and SP1 knock-down attenuated CTR1 expression.ConclusionThe p53 might function as a negative regulator in CTR1 mediated cisplatin absorption, and the p53-SP1-CTR1 axis is a target for cisplatin resistance.

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Section: Discussionmentioning

confidence: 99%

p53 inhibits CTR1-mediated cisplatin absorption by suppressing SP1 nuclear translocation in osteosarcoma

et al. 2023

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“…ROS, especially H 2 O 2 , are transmitted by a redox sensor to facilitate the trafficking and signaling of VEGF receptor type 2, which is important for reparative angiogenesis. [ 28 ] In general, the formation and removal of cellular ROS are regulated by pro‐oxidant and antioxidant enzymes such as CAT, NADPH oxidases, SOD, etc, [ 28 ] contributing to maintain redox homeostasis and regulate normal cellular function. However, the role of oxidative stress in diabetic patients with critical limb ischemia is an imbalance between pro‐oxidative and antioxidant effects, leading to tissue and cellular damage.…”

Section: Discussionmentioning

confidence: 99%

Redox Modulatory Cu(II)‐Baicalein Microflowers Prepared in One Step Effectively Promote Therapeutic Angiogenesis in Diabetic Mice

Liu

Guo

et al. 2022

Adv Healthcare Materials

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Reactive oxygen species (ROS) have been implicated in multiple cellular processes, and an imbalance in redox homeostasis gives rise to diseases, therefore, reestablishing redox homeostasis is a way to cure. Here, copper‐based metal‐organic networks (Cu‐MON) are generated by one‐step reaction using anti‐inflammatory and antioxidant baicalein as organic ligand and pro‐angiogenic copper as metal ions. Phosphate buffered saline is required for triggering Cu‐MON formation, and baicalein regulates the morphology and particle size of Cu‐MON. Cu‐MON are composed of Cu‐baicalein complexes (82.08 wt%) and Cu3(PO4)2·3H2O (17.92 wt%), thus exhibit a variable catalase‐like activity against different H2O2 levels due to the reversible change between Cu2+/Cu1+/Cu0 species. Intramuscular injection of Cu‐MON significantly increases blood flow of ischemic limb in diabetic mice, enhances the relative activities of redox‐related enzymes in ischemic muscle, thus effectively ameliorating the oxidative damage. Taken together, through moderate and dynamic “precise homeostasis regulation of cells,” Cu‐MON can be an efficient therapeutic strategy for peripheral arterial disease with diabetic complications.

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“…The former is responsible for protein coding in humans (29). A recent study revealed that CTR1 could function as a redox sensor to drive neovascularization (30). A strong correlation between CTR1 and Programmed death-ligand 1 (PD-L1) paved the way for clinical trials to evaluate Cu chelators as immune checkpoint inhibitors (31).…”

Section: Discussionmentioning

confidence: 99%

Systematic Pan-Cancer Analysis Identifies SLC31A1 as a Biomarker in Multiple Tumor Types

Kong

Ren

Jia

et al. 2022

Preprint

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Background Solute Carrier Family 31 Member 1 (SLC31A1) has recently been identified as a cuproptosis-regulatory gene. Recent studies have indicated that SLC31A1 may play a role in colorectal and lung cancer tumorigenesis. However, the role of SLC31A1 and its cuproptosis-regulatory functions in multiple tumor types remains to be further elucidated. Methods In this study, we used some website tools such as HPA, GEPIA2 and cBioPortal to estimate the expression, genetic alteration and prognostic in multiple cancer types. TIMER2 was used to evaluate the cancer-associated fibroblast infiltration. DAVID and BioGRID were used to conduct functional analysis and constructe the PPI network, respectively. Results In general, the TCGA datasets showed increased SLC31A1 expression in tumor tissues compared with non-tumor tissues in most tumor types. In patients with tumor types including Adrenocortical Carcinoma (ACC), Low-Grade Glioma (LGG), or Mesothelioma (MESO), higher SLC31A1 expression was correlated with shorter overall survival (OS) and disease-free survival (DFS). Moreover, the expression of SLC31A1 was also implicated to be positively correlated with the infiltration of fibroblasts into tumor tissues. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that SLC31A1 co-expressed genes were involved in protein binding, integral components of the membrane, metabolic pathways, and protein processing in the endoplasmic reticulum. Protein-protein interaction network analysis showed that SLC31A1 interacted with Copper Chaperone for Superoxide Dismutase (CCS), and Erb-B2 Receptor Tyrosine Kinase 3 (ERBB3), which had been known to be associated with copper transportation and tumorigenesis. Conclusions These findings demonstrated that SLC31A1 is associated with multiple tumor types and prognosis. SLC31A1 may be a potential key biomarker and therapeutic target in cancers. As a result, it will be a novel new therapy for cancer patients to improve the prognosis of cancer patients.

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Cysteine oxidation of copper transporter CTR1 drives VEGFR2 signalling and angiogenesis

Cited by 102 publications

References 62 publications

p53 inhibits CTR1-mediated cisplatin absorption by suppressing SP1 nuclear translocation in osteosarcoma

p53 inhibits CTR1-mediated cisplatin absorption by suppressing SP1 nuclear translocation in osteosarcoma

Redox Modulatory Cu(II)‐Baicalein Microflowers Prepared in One Step Effectively Promote Therapeutic Angiogenesis in Diabetic Mice

Systematic Pan-Cancer Analysis Identifies SLC31A1 as a Biomarker in Multiple Tumor Types

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