NEDD4L inhibits glycolysis and proliferation of cancer cells in oral squamous cell carcinoma by inducing ENO1 ubiquitination and degradation

Zhang, Guangping; Zhao, Xin; Liu, Weixian

doi:10.1080/15384047.2022.2054244

Cited by 26 publications

(21 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, the consistent increase in lactate concentration after stimulation of the cells known to induce an increase in glycolysis implies that lactate serves as a valid marker of long-term glycolytic activation of immune cells. In line with our work, several recent studies have confirmed a robust association between the rate of glycolysis and lactate levels [45][46][47] . Interestingly, the observed variation in lactate implies large variations in glycolytic metabolism of immune cells in humans.…”

Section: Discussionsupporting

confidence: 92%

Glycolytic activity in human immune cells: inter-individual variation and functional implications during health and diabetes

et al. 2022

View full text Add to dashboard Cite

An increase in glucose uptake driving aerobic glycolysis is a robust hallmark of immune cell activation. The glycolytic response supports functional alterations of the innate immune cells including the production and release of cytokines. Large inter-individual differences in the magnitude of this cytokine response are known to exist. In addition, the presence of disease is known to impact on immune cell function. Whether variation in metabolic responses of immune cells exist between individuals during health or disease is currently unknown. Here, we explore inter-individual differences in the glycolytic rate of immune cells using lactate production as readout upon activation using a variety of different stimuli. Glycolytic responses are subsequently associated to functional immune cell responses in healthy humans. In addition, we determined the glycolytic rate of immune cells and its association with immune function using patients diagnosed with diabetes mellitus. Based on the relative increase in lactate production after activation, distinct clusters of low, intermediate, and high responders could be identified, illustrating the existence of variation in glycolytic responses in healthy subjects. Interestingly, the production of cytokines mirrored these high-, intermediate-, and low-lactate patterns after pathogenic stimulation. In patients with diabetes mellitus, a reduced correlation was found between lactate and cytokine production, specifically for IL-6. Furthermore, based on the relative increase in lactate production, variability in the glycolytic response was reduced compared to healthy subjects. In conclusion, our results show a specific association between the glycolytic rate and function in human immune cells after stimulation with different pathogens. In addition to demonstrating the existence of glycolytic variability and specificity depending on the type of stimulus, the association between glycolysis and function in innate immune cells is altered during the presence of diabetes.

show abstract

Section: Discussionsupporting

confidence: 92%

Glycolytic activity in human immune cells: inter-individual variation and functional implications during health and diabetes

et al. 2022

View full text Add to dashboard Cite

show abstract

“…21 Besides, NEDD4L has been revealed to attenuate the proliferation and glycolysis of oral squamous cell carcinoma cells to exert the tumor-suppressive functions. 22 Further, low-NEDD4L expression has been suggested to be linked to the poor survival of clear cell renal cell carcinoma patients, whereas NEDD4L overexpression weakened the proliferation and migration abilities of clear cell renal cell carcinoma cells. 23 Consistently, this study indicated the tumor suppressor role of NEDD4L in BLCA.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

You

et al. 2023

Environmental Toxicology

View full text Add to dashboard Cite

Purpose This study identified the function of neural precursor cell expressed developmentally down‐regulated 4‐like (NEDD4L) on bladder cancer (BLCA). Methods NEDD4L expression in BLCA patients was scrutinized. The function of NEDD4L on the viability, apoptosis, migration and invasion of BLCA cells was evaluated by cell counting kit‐8, flow cytometry and Transwell assays. The effect of NEDD4L on the cisplatin (DDP) resistance of the DDP‐resistant BLCA cells was explored. The influence of NEDD4L on the p62/Keap1/Nrf2 pathway activity in BLCA cells was tested by Western blot. Rescue experiments were implemented to verify whether NEDD4L regulated BLCA cell malignant behavior by mediating the Keap1/Nrf2 pathway activity via p62. The effect of NEDD4L on the growth and the p62/Keap1/Nrf2 pathway activity in vivo was researched in xenograft tumor nude mice models. Results The down‐regulated NEDD4L in BLCA patients was associated with unfavorable survival. NEDD4L suppressed the viability (inhibition rate 57.1%/49.0%), migration (inhibition rate 49.7%/77.1%), invasion (inhibition rate 50.6%/75.7%), promoted the apoptosis of T24/5637 cells (promotion rate 243.8%/201.9%), reduced IC 50 of DDP‐resistant T24/5637 cells from 132.2/101.8 to 57.81/59.71 μM, respectively, and inactivated the p62/Keap1/Nrf2 pathway in T24/5637 cells. p62 up‐regulation partially abrogated the inhibition of NEDD4L on the Keap1/Nrf2 pathway activity, the malignant behavior of BLCA cells, and the DDP resistance of DDP‐resistant BLCA cells. NEDD4L overexpression inhibited the tumor growth and the p62/Keap1/Nrf2 pathway activity in vivo in BLCA. Conclusion NEDD4L inhibits the progression of BLCA by inactivating the p62/Keap1/Nrf2 pathway. It may be an effective target for BLCA treatment.

show abstract

“…ENO1, also referred to as 2-phospho-D-glycerate hydrolase, is a multifunctional oncoprotein that is present both at the cell surface and in the cytoplasm, contributing to it displaying seven out of ten “hallmarks of cancer” [ 37 , 38 ]. Many studies have demonstrated that the localization and overexpression of ENO1 on the cancer cell surface make it a potential prognostic and diagnostic cancer biomarker as well as an accessible oncotarget [ 39 , 40 ]. Using TCGA HNSCC database, we also found upregulated ENO1 in HNSCC tissues relative to normal counterparts (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

Gao

Yang

Tang

et al. 2023

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Enolase 2 (ENO2) is a crucial glycolytic enzyme in cancer metabolic process and acts as a “moonlighting” protein to play various functions in diverse cellular processes unrelated to glycolysis. ENO2 is highly expressed in head and neck squamous cell carcinoma (HNSCC) tissues relative to normal tissues; however, its impact and underlying regulatory mechanisms in HNSCC malignancy remain unclear. Methods Molecular alterations were examined by bioinformatics, qRT-PCR, western blotting, immunofluorescence, immunohistochemistry, immunoprecipitation, and ChIP-PCR assays. Metabolic changes were assessed by intracellular levels of ATP and glucose. Animal study was used to evaluate the therapeutic efficacy of the ENO inhibitor. Results ENO2 is required for HNSCC cell proliferation and glycolysis, which, surprisingly, is partially achieved by controlling PKM2 protein stability and its nuclear translocation. Mechanistically, loss of ENO2 expression promotes PKM2 protein degradation via the ubiquitin-proteasome pathway and prevents the switch of cytoplasmic PKM2 to the nucleus by inactivating AKT signaling, leading to a blockade in PKM2-mediated glycolytic flux and CCND1-associated cell cycle progression. In addition, treatment with the ENO inhibitor AP-III-a4 significantly induces HNSCC remission in a preclinical mouse model. Conclusion Our work elucidates the signaling basis underlying ENO2-dependent HNSCC development, providing evidence to establish a novel ENO2-targeted therapy for treating HNSCC.

show abstract

NEDD4L inhibits glycolysis and proliferation of cancer cells in oral squamous cell carcinoma by inducing ENO1 ubiquitination and degradation

Cited by 26 publications

References 51 publications

Glycolytic activity in human immune cells: inter-individual variation and functional implications during health and diabetes

Glycolytic activity in human immune cells: inter-individual variation and functional implications during health and diabetes

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

Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

Contact Info

Product

Resources

About