Autophagic degradation of CCN2 (cellular communication network factor 2) causes cardiotoxicity of sunitinib

Xu, Zhifei; Jin, Ying; Gao, Zizheng; Zeng, Yan; Du, Jiangxia; Hao, Yan; Chen, Xueqin; Li, Ping; Lin, Nengming; Yang, Bo; He, Qiaojun; Luo, Peihua

doi:10.1080/15548627.2021.1965712

Cited by 27 publications

(15 citation statements)

References 98 publications

(114 reference statements)

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“…Li et al (2022) found that magnesium isoglycyrrhizinate exerts therapeutic effects on crizotinibinduced hepatotoxicity by decreasing the level of ROS. Xu et al (2022) also reported that GA significantly mitigated Sunitinibinduced cardiotoxicity. We have proved previously that GA could alleviate liver damage through upregulating Nrf2, defensing oxidative stress and inhibiting apoptosis (Cao et al, 2016;Yan et al, 2021).…”

Section: Discussionmentioning

confidence: 88%

Sunitinib induced hepatotoxicity in L02 cells via ROS-MAPKs signaling pathway

Tang

Yang²,

Guo³

et al. 2022

Front. Pharmacol.

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Sunitinib is a multi-targeted tyrosine kinase inhibitor with remarkable anticancer activity, while hepatotoxicity is a potentially fatal adverse effect of its administration. The aim of this study was to elucidate the mechanism of hepatotoxicity induced by Sunitinib and the protective effect of glycyrrhetinic acid (GA). Sunitinib significantly reduced the survival of human normal hepatocytes (L02 cells), induced the increase of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). Chloroquine (CQ) and Z-VAD-FMK were applied to clarify the cell death patterns induced by Sunitinib. Sunitinib significantly induced L02 cells death by triggering apoptosis and autophagy acted as a self-defense mechanism to promote survival. Sunitinib exposure caused excessive ROS generation which activated mitogen-activated protein kinases (MAPKs) signaling. Mechanistically, SP600125 (JNK inhibitor) and SB203580 (p38 inhibitor) respectively blocked apoptosis and autophagy induced by Sunitinib. And inhibition of ROS by NAC pretreatment ameliorated the effect of Sunitinib on MAPKs phosphorylation. GA alleviated Sunitinib-induced cell damage by inhibiting apoptosis and autophagy. These results suggested ROS/MAPKs signaling pathway was responsible for Sunitinib-induced hepatotoxicity and GA could be a preventive strategy to alleviate liver injury caused by Sunitinib.

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Section: Discussionmentioning

confidence: 88%

Sunitinib induced hepatotoxicity in L02 cells via ROS-MAPKs signaling pathway

Tang

Yang²,

Guo³

et al. 2022

Front. Pharmacol.

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“…Recently, CCN family has been reported to be closely related to autophagy 16,26,27 . In addition, autophagy was reported to be regulated by ERK signaling 28 .…”

Section: Resultsmentioning

confidence: 99%

“…Recently, CCN family has been reported to be closely related to autophagy. 16,26,27 In addition, autophagy was reported to be regulated by ERK signaling. 28 To probe the signaling downstream events of CCN1-mediated osteogenesis, we investigated the effect of CCN1 on autophagy.…”

Section: Ccn1 Induces Autophagy Via Erk Signaling To Promote Osteogen...mentioning

confidence: 99%

Cellular communication network factor 1 interlinks autophagy and ERK signaling to promote osteogenesis of periodontal ligament stem cells

et al. 2022

J of Periodontal Research

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Objectives: To investigate the effects of cellular communication network factor 1 (CCN1), a critical matricellular protein, on alveolar bone regeneration, and to elucidate the underlying molecular mechanism. Background:In the process of orthodontic tooth movement, bone deposition on the tension side of human periodontal ligament stem cells (hPDLSCs) ensured high efficiency and long-term stability of the treatment. The matricellular protein CCN1 is responsive to mechanical stimulation, exhibiting important tasks in bone homoeostasis.However, the role and mechanism of CCN1 on alveolar bone remodeling of hPDLSCs remains unclear. Methods: The expression and distribution of CCN1 in rat periodontal ligament were detected by immunofluorescence staining and immunohistochemical staining. ELISA verified the secretion of CCN1 triggered by stretch loading. To examine the mineralization ability of hPDLSCs induced by CCN1, Western blotting, qRT-PCR, ARS, and ALP staining were performed. CCK-8 and cell migration assay were performed to detect the cell proliferation rate and the wound healing. PI3K/Akt, MAPK, and autophagy activation were examined via Western blotting and immunofluorescence. Results: Mechanical stimuli induced the release of CCN1 into extracellular environment by hPDLSCs. Knockdown of CCN1 attenuated the osteogenesis of hPDLSCs while rhCCN1 enhanced the expression of Runx2, Col 1, ALPL, and promoted the mineralization nodule formation. CCN1 activated PI3K/Akt and ERK signaling, and blockage of PI3K/Akt signaling reversed the accelerated cell migration triggered by CCN1. The enhanced osteogenesis induced by CCN1 was abolished by ERK signaling inhibitor PD98059 or autophagy inhibitor 3-MA. Further investigation demonstrated PD98059 abrogated the activation of autophagy. Conclusion:This study demonstrated that CCN1 promotes osteogenesis in hPDLSCs via autophagy and MAPK/ERK pathway.

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“…Although most studies showed that autophagy has a protective effect on neurons, but the existence of autophagic cell death (ACD) indicated that cell death is also executed through autophagy, such as an increase in autophagic flow and autophagic markers is found in dying cells, and inhibition of autophagy by pharmacological inhibitors or genetic methods can also rescue and prevent cell death (Shen et al, 2011;Hensley and Harris-White, 2015). In a variety of disease models, the damage to target organs by pathogenic factors has been further mitigated by pharmacological attenuation of autophagy levels (Li et al, 2017;Xu et al, 2022). LDH and apoptosis assays have been used in several studies to measure the extent of cell damage (Kumar et al, 2018;Zhang et al, 2020), as previously described, neurons cultured in leucine-deficient 10.3389/fncel.2022.1060712 medium showed a significant increase in cellular LDH release and apoptosis, and after administration of autophagy inhibitors, cellular LDH release and apoptosis decreased significantly, suggesting that leucine deficiency induces excessive autophagy in neurons and then causes damage.…”

Section: Discussionmentioning

confidence: 99%

Leucine mediates cognitive dysfunction in early life stress-induced mental disorders by activating autophagy

Wang¹,

Wang²,

Xie³

et al. 2023

Front. Cell. Neurosci.

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ObjectivesTo explore the relationship between leucine in cerebrospinal fluid (CSF) and cognitive dysfunction in rats with early life stress (ELS) induced mental illness, and pathophysiological mechanism involved.MethodsThe maternal separation (MS), an animal paradigm used widely as a preclinical model of ELS which is one of the important risk factors for mental disorders. Behavioral experiments including open-field test, sucrose preference, object recognition and Morris water maze tests, Nissl staining, transmission electron microscopy and WES were employed in the present study.ResultsThe behavioral results showed that MS rats were more prone to cognitive impairment and depression-and-anxiety-like behaviors than controls, including spatial self-exploration ability, memory ability, and spatial learning and memory function. Nissl staining analysis indicated that the number of neurons in the CA1 and CA3 regions of the hippocampus significantly decreased and the arrangement of nerve cells was abnormal. The leucine levels were decreased in the CSF of MS rats and highly correlated with the number of hippocampal neurons, and yet leucine supplementation improved the degree of MS-induced cognitive impairment. Furthermore, there were autophagosomes in the hippocampus of the low-leucine diet rats of the control and MS group but not in the high-leucine diet MS group by transmission electron microscopy. The protein expression of Beclin-1 in the hippocampus was significantly increased in the MS normal diet group and MS low-leucine diet group, yet decreased in the MS high-leucine diet group compared with the MS low-leucine diet group. Meanwhile, the Bcl-2/Bax ratio was significantly decreased in the control low-leucine diet group, MS normal diet group and MS low-leucine diet group. Ultimately, in vitro experiments suggested that leucine deficiency could activate neuronal autophagy including enhanced LC3II/LC3I and mRFP-GFP-LC3, which was consistent with the in vivo results, and the cell apoptosis rate and lactate dehydrogenase (LDH) cytotoxicity were also increased with leucine deficiency, while the above effects could be partly reversed by autophagy inhibitor treatment.ConclusionsMS model caused adult male rats to be susceptible to cognitive dysfunction, which may regulate autophagy in hippocampal neurons through leucine metabolism in CSF.

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Autophagic degradation of CCN2 (cellular communication network factor 2) causes cardiotoxicity of sunitinib

Cited by 27 publications

References 98 publications

Sunitinib induced hepatotoxicity in L02 cells via ROS-MAPKs signaling pathway

Sunitinib induced hepatotoxicity in L02 cells via ROS-MAPKs signaling pathway

Cellular communication network factor 1 interlinks autophagy and ERK signaling to promote osteogenesis of periodontal ligament stem cells

Leucine mediates cognitive dysfunction in early life stress-induced mental disorders by activating autophagy

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