<scp>NEDD4L</scp> inhibits migration, invasion, cisplatin resistance and promotes apoptosis of bladder cancer cells by inactivating the p62/Keap1/Nrf2 pathway

Wu, Qi; Zhang, Huijiang; You, Shengjie; Xu, Zhaoyu; Liu, Xiang; Chen, Xuedong; Zhang, Weili; Ye, Junjie; Zhou, Xiaoqing

doi:10.1002/tox.23796

Cited by 14 publications

(7 citation statements)

References 55 publications

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“… 33 NEDD4L inhibits bladder cancer progression by inactivating the p62/Keap1/Nrf2 pathway. 34 Although these reports showed a conflicting conclusion of NEDD4L on cell proliferation or migration, we speculated that the NEDD4L may exert different roles in different cells.…”

Section: Discussionmentioning

confidence: 87%

NEDD4L is a promoter for angiogenesis and cell proliferation in human umbilical vein endothelial cells

Liu,

Song,

Zhou

et al. 2024

J Cellular Molecular Medi

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Dysregulated angiogenesis leads to neovascularization, which can promote or exacerbate various diseases. Previous studies have proved that NEDD4L plays an important role in hypertension and atherosclerosis. Hence, we hypothesized that NEDD4L may be a critical regulator of endothelial cell (EC) function. This study aimed to define the role of NEDD4L in regulating EC angiogenesis and elucidate their underlying mechanisms. Loss‐ and gain‐of‐function of NEDD4L detected the angiogenesis and mobility role in human umbilical vein endothelial cells (HUVECs) using Matrigel tube formation assay, cell proliferation and migration. Pharmacological pathway inhibitors and western blot were used to determine the underlying mechanism of NEDD4L‐regulated endothelial functions. Knockdown of NEDD4L suppressed tube formation, cell proliferation and cell migration in HUVECs, whereas NEDD4L overexpression promoted these functions. Moreover, NEDD4L‐regulated angiogenesis and cell progression are associated with the phosphorylation of Akt, Erk1/2 and eNOS and the expression of VEGFR2 and cyclin D1 and D3. Mechanically, further evidence was confirmed by using Akt blocker MK‐2206, Erk1/2 blocker U0126 and eNOS blocker L‐NAME. Overexpression NEDD4L‐promoted angiogenesis, cell migration and cell proliferation were restrained by these inhibitors. In addition, overexpression NEDD4L‐promoted cell cycle‐related proteins cyclin D1 and D3 were also suppressed by Akt blocker MK‐2206, Erk1/2 blocker U0126 and eNOS blocker L‐NAME. Our results demonstrated a novel finding that NEDD4L promotes angiogenesis and cell progression by regulating the Akt/Erk/eNOS pathways.

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Section: Discussionmentioning

confidence: 87%

NEDD4L is a promoter for angiogenesis and cell proliferation in human umbilical vein endothelial cells

Liu,

Song,

Zhou

et al. 2024

J Cellular Molecular Medi

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“…p62 promotes the growth of BCa cells by activating the Keap1/Nrf2 pathway, while overexpression of NEDD4L inactivates the p62/Keap1/Nrf2 pathway. Summarily, NEDD4L has the ability to inhibit BCa cell growth and suppress p62/Keap1/Nrf2 pathway activity, which indirectly proves that NEDD4L/p62/Keap1/Nrf2 pathway may be an effective target for the treatment of BCa ( 89 , 90 ).…”

Section: Nrf2 In Oncologymentioning

confidence: 90%

Nrf2 signaling pathway: current status and potential therapeutic targetable role in human cancers

Lin,

Wu,

et al. 2023

Front. Oncol.

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Cancer is a borderless global health challenge that continues to threaten human health. Studies have found that oxidative stress (OS) is often associated with the etiology of many diseases, especially the aging process and cancer. Involved in the OS reaction as a key transcription factor, Nrf2 is a pivotal regulator of cellular redox state and detoxification. Nrf2 can prevent oxidative damage by regulating gene expression with antioxidant response elements (ARE) to promote the antioxidant response process. OS is generated with an imbalance in the redox state and promotes the accumulation of mutations and genome instability, thus associated with the establishment and development of different cancers. Nrf2 activation regulates a plethora of processes inducing cellular proliferation, differentiation and death, and is strongly associated with OS-mediated cancer. What’s more, Nrf2 activation is also involved in anti-inflammatory effects and metabolic disorders, neurodegenerative diseases, and multidrug resistance. Nrf2 is highly expressed in multiple human body parts of digestive system, respiratory system, reproductive system and nervous system. In oncology research, Nrf2 has emerged as a promising therapeutic target. Therefore, certain natural compounds and drugs can exert anti-cancer effects through the Nrf2 signaling pathway, and blocking the Nrf2 signaling pathway can reduce some types of tumor recurrence rates and increase sensitivity to chemotherapy. However, Nrf2’s dual role and controversial impact in cancer are inevitable consideration factors when treating Nrf2 as a therapeutic target. In this review, we summarized the current state of biological characteristics of Nrf2 and its dual role and development mechanism in different tumor cells, discussed Keap1/Nrf2/ARE signaling pathway and its downstream genes, elaborated the expression of related signaling pathways such as AMPK/mTOR and NF-κB. Besides, the main mechanism of Nrf2 as a cancer therapeutic target and the therapeutic strategies using Nrf2 inhibitors or activators, as well as the possible positive and negative effects of Nrf2 activation were also reviewed. It can be concluded that Nrf2 is related to OS and serves as an important factor in cancer formation and development, thus provides a basis for targeted therapy in human cancers.

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“…Chemoresistance is a complex biological process influenced by various regulatory mechanisms. Traditional phenotypes associated with chemoresistance, such as DNA damage repair pathways, drug metabolism, oncogenes, 35 cancer stem cells, 36 and tumor suppressors, 37 have been recognized as new strategies for addressing chemoresistance. Researchers are increasingly emphasizing the relationship between chemotherapy and the tumor immune microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a prognostic model to predict chemotherapy response and identification of RAC3 as a chemotherapeutic target in bladder cancer

Chen

Huang

et al. 2023

Environmental Toxicology

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Cisplatin‐based chemotherapy is considered the primary treatment option for patients with advanced bladder cancer (BCa). However, the objective response rate to chemotherapy is often unsatisfactory, leading to a poor 5‐year survival rate. Furthermore, current strategies for evaluating chemotherapy response and prognosis are limited and inefficient. In this study, we aimed to address these challenges by establishing a chemotherapy response type gene (CRTG) signature consisting of 9 genes and verified the prognostic value of this signature using TCGA and GEO BCa cohorts. The risk scores based on the CRTG signature were found to be associated with advanced clinicopathological status and demonstrated favorable predictive power for chemotherapy response in the TCGA cohort. Meanwhile, tumors with high risk scores exhibited a tendency toward a “cold tumor” phenotype. These tumors showed a low abundance of T cells, CD8+ T cells and cytotoxic lymphocytes, along with a high abundance of cancer‐associated fibroblasts. Moreover, they displayed higher mRNA levels of these immune checkpoints: CD200, CD276, CD44, NRP1, PDCD1LG2 (PD‐L2), and TNFSF9. Furthermore, we developed a nomogram that integrated the CRTG signature with clinicopathologic risk factors. This nomogram proved to be a more effective tool for predicting the prognosis of BCa patients. Additionally, we identified Rac family small GTPase 3 (RAC3) as a biomarker in our model. RAC3 was found to be overexpressed in chemoresistant BCa tissues and enhance the chemotherapeutic resistance of BCa cells in vitro and in vivo by regulating the PAK1‐ERK1/2 pathway. In conclusion, our study presents a novel CRTG model for predicting chemotherapy response and prognosis in BCa. We also highlight the potential of combining chemotherapy with immunotherapy as a promising strategy for chemoresistant BCa and that RAC3 might be a latent target for therapeutic intervention.

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NEDD4L inhibits migration, invasion, cisplatin resistance and promotes apoptosis of bladder cancer cells by inactivating the p62/Keap1/Nrf2 pathway

Cited by 14 publications

References 55 publications

NEDD4L is a promoter for angiogenesis and cell proliferation in human umbilical vein endothelial cells

NEDD4L is a promoter for angiogenesis and cell proliferation in human umbilical vein endothelial cells

Nrf2 signaling pathway: current status and potential therapeutic targetable role in human cancers

Establishment of a prognostic model to predict chemotherapy response and identification of RAC3 as a chemotherapeutic target in bladder cancer

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