High glucose-induced apoptosis and necroptosis in podocytes is regulated by UCHL1 via RIPK1/RIPK3 pathway

Xu, Yaolin; Gao, Hongyang; Hu, Yuan; Fang, Yili; Qi, Chenyang; Huang, Jiebo; Cai, Xiaofan; Wu, Huijuan; Ding, Xiaoqiang; Zhang, Zhigang

doi:10.1016/j.yexcr.2019.06.008

Cited by 54 publications

(42 citation statements)

References 44 publications

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“…RIPK1 and RIPK3 were both critical regulators of necroptosis. As necroptosis occurred, RIPK3 level consistently increased, but RIPK1 level may increase (Xu et al, 2019;Zhang et al, 2019) or decrease (Motani et al, 2011;Tian et al, 2013) under different stimuli-inducing necroptosis. In our study, the RIPK1 expression decreased after the combination treatment of rapamycin and MK-2206.…”

Section: Discussionmentioning

confidence: 96%

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines

et al. 2020

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Neuroblastoma (NB) is the most common pediatric malignant extracranial solid tumor. Despite multi-modality therapies, the emergence of drug resistance is an obstacle in the treatment of high-risk NB patients (with MYCN amplification). In our previous study, we found that rapamycin and MK-2206 synergistically induced cell death in MYCN-amplified cell lines but the mechanisms remained unclear. In our present study, either 3-MA or necroatatin-1 blocked the cell death induced by rapamycin and MK-2206, but z-VAD-fmk did not block this cell death. The expressions of autophagy markers (ATG5, ATG7, Beclin-1, LC3 B) and the necroptosis marker RIPK3 increased and another necroptosis marker RIPK1 decreased after the combination treatment of rapamycin and MK-2206, and were accompanied by the morphological characteristics of autophagy and necroptosis. In NB xenograft tumor tissues, the expressions of autophagy and necroptosis markers were consistent with observations in vitro. These data suggested that autophagy and necroptosis contributed to the cell death induced by rapamycin and MK-2206 in NB cells. To understand the role of MYCN in this process, MYCN expression was downregulated in MYCN-amplified cell lines (NGP, BE2) using siRNAs and was upregulated in MYCN non-amplified cell lines (AS, SY5Y) using plasmid. We found the cell death induced by rapamycin and MK-2206 was MYCN-dependent. We also found that the metabolic activity in NB cells was correlated with the expression level of MYCN. This study delineates the role of MYCN in the cell death induced by combination treatment of rapamycin and MK-2206 in MYCN-amplified NB cells.

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Section: Discussionmentioning

confidence: 96%

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines

et al. 2020

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“…By suppressing intrinsic apoptosis, UCHL1 ameliorates type 2 diabetes and Alzheimer's disease. Conversely, UCHL1 promotes high-glucose-induced extrinsic apoptosis and necroptosis, which promote diabetic nephropathy (Figure 4a) [55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70]. In malignant diseases, DUBs can aggravate or ameliorate cancers, depending on their downstream RCD.…”

Section: Dubs Regulating Diverse Rcdmentioning

confidence: 99%

“…A recent study demonstrated that podocytes undergo apoptosis and necroptosis during diabetic nephropathy. Diabetic stress upregulates the levels of UCHL1, which deubiquitinates and stabilizes RIPK1 and RIPK3, consequently promoting cell death [ 59 ].…”

Section: Dubs Regulating Diverse Rcdmentioning

confidence: 99%

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

Lee

Kim

Hwang

et al. 2021

IJMS

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The mechanisms and physiological implications of regulated cell death (RCD) have been extensively studied. Among the regulatory mechanisms of RCD, ubiquitination and deubiquitination enable post-translational regulation of signaling by modulating substrate degradation and signal transduction. Deubiquitinases (DUBs) are involved in diverse molecular pathways of RCD. Some DUBs modulate multiple modalities of RCD by regulating various substrates and are powerful regulators of cell fate. However, the therapeutic targeting of DUB is limited, as the physiological consequences of modulating DUBs cannot be predicted. In this review, the mechanisms of DUBs that regulate multiple types of RCD are summarized. This comprehensive summary aims to improve our understanding of the complex DUB/RCD regulatory axis comprising various molecular mechanisms for diverse physiological processes. Additionally, this review will enable the understanding of the advantages of therapeutic targeting of DUBs and developing strategies to overcome the side effects associated with the therapeutic applications of DUB modulators.

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“…Ubiquitin C-terminal hydrolase L1(UCHL1), also known as PARK5, belongs to the peptidase C12 family [11,12] . UCHL1 acts as either an oncogene or a tumor-suppressor gene depending on the cancer types, partially because its nature of the deubiquitinating activity that inhibits proteasome mediated degradation is diverse, by the deubiquitination of proteins themselves that are affected in a variety of tumor tissues [13][14][15] . Previous report showed that UCHL1 promotes uterine serous cancer cell proliferation and cell cycle progression [16] .…”

mentioning

confidence: 99%

UCHL1 Promotes Chemoresistance to 5-Fluoruracil Based Adjuvant Chemotherapy and is a Prognostic Marker for Stage II Colon Cancer Patients

Ma¹,

Wu²,

Ding³

et al. 2021

Preprint

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Background: 5-Fluoruracil based adjuvant chemotherapy after radical resection is recommended for stage II colon cancer patients with high risk of recurrence. Up to now, novel biomarkers still needed for better stratification for improving prognosis. Methods: Here we report that UCHL1 is an independent prognostic factor for stage II colon cancer patients and promotes chemoresistance both in vitro and in vivo. Results: Our study indicated that UCHL1 is significant up regulated in 96 pairs of stage II colon cancer patients who received postoperative 5-FU based chemotherapy. Stage II colon cancer patients with high UCHL1 expression showed high recurrence rate after chemotherapy. Multivariate Cox regression analysis showed that UCHL1 is an independent prognostic factor for overall survival (P=0.008) and disease-free survival (P=0.001). 5-FU based chemoresistance is examined in colon cancer cell lines (RKO and LoVo) with down regulation of UCHL1 by cytotoxicity test. Down regulation of UCHL1 exhibited decreased cell viability, elevated cell apoptosis rate, increased G2/M-phase and elevated level of cleaved caspase 3 and PARP when treated with 5-FU. Furthermore, the results in xenograft model are consistent with results in vitro.Conclusions: UCHL1 potentially contributing to identify recurrence risk and predict the benefit for postoperative 5-FU based adjuvant chemotherapy in stage II colon cancer patients.

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High glucose-induced apoptosis and necroptosis in podocytes is regulated by UCHL1 via RIPK1/RIPK3 pathway

Cited by 54 publications

References 44 publications

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

UCHL1 Promotes Chemoresistance to 5-Fluoruracil Based Adjuvant Chemotherapy and is a Prognostic Marker for Stage II Colon Cancer Patients

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