Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth

Francisco, Michelle A; Wanggou, Siyi; Fan, Jerry J.; Dong, Weifan; Chen, Xin; Momin, Ali; Abeysundara, Namal; Min, Hyun-Kee; Chan, Jade; McAdam, Rochelle F.; Sia, Marian; Pusong, Ronwell J.; Liu, Shixuan; Patel, Nish; Ramaswamy, Vijay; Kijima, Noriyuki; Wang, Lu-Yang; Song, Yuanquan; Kafri, Ran; Taylor, Michael D.; Li, Xuejun; Huang, Xi

doi:10.1084/jem.20190971

Cited by 29 publications

(29 citation statements)

References 50 publications

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“…Increased production of ROS is a hallmark of cell senescence, which also regulates the activation of CLICs. In recent years, the biological functions of CLICs in the pathological progression of diseases, such as CLIC4 regulation of pulmonary hypertension by activating Arf6 [25], CLIC2 inhibition of cardiac muscle ryanodine receptor [26], as well as CLIC1 and CLIC3 involvement in cancer development [27][28][29], have sparked considerable interests. Even though the role of CLICs in cancer has been extensively discussed, its role in age-related CVD has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

CLIC1 Inhibition Protects Against Cellular Senescence and Endothelial Dysfunction Via the Nrf2/HO-1 Pathway

Ding

et al. 2021

Cell Biochem Biophys

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Chloride intracellular channel 1 (CLIC1) is a sensor of oxidative stress in endothelial cells (EC). However, the mechanism by which CLIC1 mediate the regulation of endothelial dysfunction has not been established. In this study, overexpressed CLIC1 impaired the ability of the vascular cells to resist oxidative damage and promoted cellular senescence. Besides, suppressed CLIC1 protected against cellular senescence and dysfunction in Human Umbilical Vein Endothelial Cells (HUVECs) through the Nrf2/HO-1 pathway. We also found that ROS-activated CLIC1-induced oxidative stress in HUVECs. Nrf2 nuclear translocation was inhibited by CLIC1 overexpression, but was enhanced by IAA94 (CLICs inhibitor) treatment or knockdown of CLIC1. The Nrf2/HO-1 pathway plays a critical role in the anti-oxidative effect of suppressing CLIC1. And inhibition of CLIC1 decreases oxidative stress injury by downregulating the levels of ROS, MDA, and the expression of EC effectors (ICAM1 and VCAM1) protein expression and promotes the activity of superoxide dismutase (SOD). The AMPK-mediated signaling pathway activates Nrf2 through Nrf2 phosphorylation and nuclear translocation, which is also regulated by CLIC1. Moreover, the activation of CLIC1 contributes to H 2 O 2-induced mitochondrial dysfunction and activation of mitochondrial fission. Therefore, elucidation of the mechanisms by which CLIC1 is involved in these pivotal pathways may uncover its therapeutic potential in alleviating ECs oxidative stress and age-related cardiovascular disease development.

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Section: Discussionmentioning

confidence: 99%

CLIC1 Inhibition Protects Against Cellular Senescence and Endothelial Dysfunction Via the Nrf2/HO-1 Pathway

Ding

et al. 2021

Cell Biochem Biophys

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“…Numerous studies have confirmed that CLIC1 was upregulated in a variety of tumors and can be used as a poor marker, which involved with the regulation of angiogenesis, migration, invasion and apoptosis 14,25 . Francisco et al have revealed that overexpression of CLIC1 could cooperate with EAG2, leading to the dysregulation of cells volume homeostasis, RNA biosynthesis, and the activation of the p38 MAPK pathway, thus promoting cell proliferation and tumor growth in human medulloblastoma 26 . Moreover, CLIC1 was also affirmed to be a secreted protein, existed in extracellular vesicles comprising exosomes and microvesicles which released by glioblastoma multiforme (GBM) cells, and could regulate the properties of cancer stem cells (CSCs) and pro‐tumorigenic response in GBM progression 16 .…”

Section: Discussionmentioning

confidence: 99%

Exosomal CLIC1 released by CLL promotes HUVECs angiogenesis by regulating ITGβ1‐MAPK/ERK axis

Geng

Feng

Zhang

et al. 2020

The Kaohsiung J of Med Scie

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Accumulating evidences have suggested that exosomes are closely associated with tumor progression by affecting cell‐cell communication. Here, we aimed to investigate the roles and regulatory mechanism of exosomes released from chronic lymphocytic leukemia (CLL). The expression levels of genes and proteins in cells and exosomes were examined by quantitative real‐time PCR and Western blotting, respectively. MEC‐1 cell‐derived exosomes were obtained and co‐cultured with human umbilical vein endothelial cells (HUVECs), then the capabilities of cell proliferation, metastasis and angiogenesis of HUVECs were measured by CCK‐8, wound healing, transwell and tube formation assay, respectively. Chloride intracellular channel 1 (CLIC1) was significantly increased in CLL patients and markedly enriched in exosomes secreted by CLL cells. Exosomal CLIC1 secreted from MEC‐1 cells were successfully transferred into HUVECs and significantly promoted the phenotypes of proliferation, metastasis and angiogenesis of HUVECs. Mechanically, exosomal CLIC1 secreted from MEC‐1 cells obviously activated MAPK/ERK signaling through upregulating integrin β1 (ITGβ1) expression in HUVECs. Furthermore, rescue experiments revealed that either silencing ITGβ1 or PD98059 treatment obviously reversed the regulatory effects of exosomal CLIC1 secreted from MEC‐1 cells in HUVECs. In conclusion, CLL cell‐derived exosomes accelerated HUVECs metastasis and angiogenesis through transferring CLIC1 to regulate ITGβ1‐MAPK/ERK signaling, indicating that CLIC1 may be a therapeutic target of CLL exosomes in the tumor microenvironment.

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“…The tumor-promoting role of CLIC1 has been reported in a variety of tumors [12,14,15]. Indirectly, miR-124 inhibits the proliferation, migration, and invasion of liver cancer cells by targeting CLIC1 [24];…”

Section: Discussionmentioning

confidence: 99%

“…The expression of CLIC1 is upregulated in a variety of different cancers, such as oral squamous cell carcinoma [8], epithelial ovarian cancer [9], gastric cancer [10], gallbladder cancer [11], pancreatic cancer [12], and gliomas [13], and increased CLIC1 levels are associated with a poor prognosis in these patients. Moreover, knockout of CLIC1 inhibits medulloblastoma growth in xenograft and genetically engineered mouse models [14].…”

Section: Introductionmentioning

confidence: 99%

Acetylation stabilizes chloride intracellular channel 1 that exerts a tumor-promoting role by activation of nuclear factor kappa B in cervical cancer

Wang¹,

Li²,

Xu³

et al. 2020

Preprint

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Background: Cervical cancer remains a major cause of cancer-related death in women, especially in developing countries. Previously, we identified that acetylation levels of chloride intracellular channel 1 (CLIC1) at lysine 131 were increased in cervical cancer tissues by using the label-free proteomics approach. The aim of this study was further to determine the role of CLIC1 expression and its acetylation in cervical cancer. Methods: CLIC1 expression and its implications on prognosis in cervical cancer were analyzed using Gene Expression Profiling Interactive Analysis (GEPIA) database (gepia.cancer-pku.cn). The effect of CLIC1 on cells was evaluated by Cell Counting Kit (CCK)-8, flow cytometry, wound healing assay, transwell assay, western blotting, and co-immunoprecipitation (Co-IP). In vivo tumor growth was assessed in mouse xenograft models. Results: We found that CLIC1 expression was increased in cervical cancer tissues and cells. The knockdown of CLIC1 significantly reduced cell proliferation, migration, invasion, and in vivo tumorigenesis of cervical cancer cells. Molecularly, nuclear factor kappa B (NF-κB) activity was positively regulated by CLIC1. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB activation, attenuated the tumor-promoting effect of CLIC1. Moreover, CLIC1 acetylation at K131 was upregulated in cervical cancer, which stabilized CLIC1 by inhibiting ubiquitylation. The substitution of K131 inhibited CLIC1 ubiquitylation and promoted cell proliferation, migration, and invasion, and tumor growth. In addition, we identified that acetyltransferase HAT1 was responsible for CLIC1 acetylation at K131. Conclusion: This finding shows that CLIC1 is a tumor promoter in cervical cancer, indicating a potential strategy to treat cervical cancer by regulating CLIC1 expression or acetylation.

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Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth

Cited by 29 publications

References 50 publications

CLIC1 Inhibition Protects Against Cellular Senescence and Endothelial Dysfunction Via the Nrf2/HO-1 Pathway

CLIC1 Inhibition Protects Against Cellular Senescence and Endothelial Dysfunction Via the Nrf2/HO-1 Pathway

Exosomal CLIC1 released by CLL promotes HUVECs angiogenesis by regulating ITGβ1‐MAPK/ERK axis

Acetylation stabilizes chloride intracellular channel 1 that exerts a tumor-promoting role by activation of nuclear factor kappa B in cervical cancer

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