Novel interaction between neurotrophic factor-α1/carboxypeptidase E and serotonin receptor, 5-HTR1E, protects human neurons against oxidative/neuroexcitotoxic stress via β-arrestin/ERK signaling

Sharma, Vinay; Yang, Xiaoling; Kim, Soo‐Kyung; Mafi, Amirhossein; Saiz-Sánchez, Daniel; Villanueva-Anguita, Patricia; Xiao, Lan; Toulabi, Leila; Inoue, Asuka; Goddard, William A.; Loh, Y. Peng

doi:10.1007/s00018-021-04021-3

Cited by 21 publications

(46 citation statements)

References 48 publications

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“…We propose that CPE controls its targets, such as c-MYC and Cyclin D1, through binding a receptor to activate downstream signaling. We have recently found that CPE activates a receptor HTR1E to activate the ERK pathway [ 48 ]. ERK/c-MYC and ERK/Cyclin D1 signaling are well known in promoting proliferation and migration in cancer cells, and HTR1E has been found in human cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Exosomal Carboxypeptidase E (CPE) and CPE-shRNA-Loaded Exosomes Regulate Metastatic Phenotype of Tumor Cells

Hareendran

Albraidy

Yang

et al. 2022

IJMS

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Background: Exosomes promote tumor growth and metastasis through intercellular communication, although the mechanism remains elusive. Carboxypeptidase E (CPE) supports the progression of different cancers, including hepatocellular carcinoma (HCC). Here, we investigated whether CPE is the bioactive cargo within exosomes, and whether it contributes to tumorigenesis, using HCC cell lines as a cancer model. Methods: Exosomes were isolated from supernatant media of cancer cells, or human sera. mRNA and protein expression were analyzed using PCR and Western blot. Low-metastatic HCC97L cells were incubated with exosomes derived from high-metastatic HCC97H cells. In other experiments, HCC97H cells were incubated with CPE-shRNA-loaded exosomes. Cell proliferation and invasion were assessed using MTT, colony formation, and matrigel invasion assays. Results: Exosomes released from cancer cells contain CPE mRNA and protein. CPE mRNA levels are enriched in exosomes secreted from high- versus low-metastastic cells, across various cancer types. In a pilot study, significantly higher CPE copy numbers were found in serum exosomes from cancer patients compared to healthy subjects. HCC97L cells, treated with exosomes derived from HCC97H cells, displayed enhanced proliferation and invasion; however, exosomes from HCC97H cells pre-treated with CPE-shRNA failed to promote proliferation. When HEK293T exosomes loaded with CPE-shRNA were incubated with HCC97H cells, the expression of CPE, Cyclin D1, a cell-cycle regulatory protein and c-myc, a proto-oncogene, were suppressed, resulting in the diminished proliferation of HCC97H cells. Conclusions: We identified CPE as an exosomal bioactive molecule driving the growth and invasion of low-metastatic HCC cells. CPE-shRNA loaded exosomes can inhibit malignant tumor cell proliferation via Cyclin D1 and c-MYC suppression. Thus, CPE is a key player in the exosome transmission of tumorigenesis, and the exosome-based delivery of CPE-shRNA offers a potential treatment for tumor progression. Notably, measuring CPE transcript levels in serum exosomes from cancer patients could have potential liquid biopsy applications.

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Section: Discussionmentioning

confidence: 99%

Exosomal Carboxypeptidase E (CPE) and CPE-shRNA-Loaded Exosomes Regulate Metastatic Phenotype of Tumor Cells

Hareendran

Albraidy

Yang

et al. 2022

IJMS

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“…Protecting neurons from death during oxidative and neuroexcitotoxic stress is key for preventing cognitive dysfunction [ 27 ]. Oxidative stress can promote the production of Aβ, promote cell apoptosis, and reduce the expression of LDL-C receptor related protein 1 [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Explore the Mechanism of β-Asarone on Improving Cognitive Dysfunction in Rats with Diabetic Encephalopathy

Cai

Xia

et al. 2022

ADR

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Background: The number of people with diabetes is increasing, and many patients have significantly impaired cognitive function. For patients with diabetic encephalopathy (DE), simply lowering blood sugar does not improve learning and memory. Studies have shown that β-asarone can significantly improve cognitive impairment in patients with DE, but the specific mechanism of action is unclear. Objective: This experiment hopes to use a variety of experimental methods to clarify the protective effect and mechanism of β-asarone on brain neurons during the development of DE disease. Methods: A high-sugar and high-fat diet and streptozotocin injection-induced DE rat model was used. β-asarone was administered for four weeks. The experiment used the Morris water maze test, biochemical index detection, and many methods to evaluate the neuroprotective effect of β-asarone on DE rats from various aspects and understand its mechanism. Results: β-asarone reduced neuronal cell damage and significantly improved the learning and memory ability of DE rats. In addition, β-asarone can reduce the oxidative stress response and amyloid-β accumulation in the brain of DE model rats and increase the content of brain-derived neurotrophic factor (BDNF) in the brain tissue, thereby reducing neuronal cell apoptosis and playing a protective role. Conclusion: β-asarone can reduce the accumulation of oxidative stress and amyloid-β in the brain, increase the content of BDNF, reduce the apoptosis of neuronal cells, and exert neuronal protection, thereby improving the learning and memory ability of DE model rats.

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“…Molecular modeling studies predicted that NF-α1/CPE interacts with 5-HTR1E, outside of its serotonin pocket, and stabilized by several salt bridges and hydrogen bonds. Moreover, molecular dynamic studies revealed strong coupling of the intracellular loop 3 of HTR1E with β-arrestin1, indicating potential activation of β-arrestin1 ( Sharma et al, 2021 ). Immunohistochemical analysis of human hippocampus showed that NFα1/CPE and 5-HTR1E were colocalized on the cell membrane of neurons, suggesting a functional role.…”

Section: Role Of Neurotrophic Factor-α1/carboxypeptidase E and Its Re...mentioning

confidence: 99%

“…In addition, co-immunoprecipitation, and pull-down assays in HEK293 cells indicate that NFα1/CPE binds with 5-HTR1E in a saturable, high-affinity manner, with a Kd 13.82 nM. Cell biological studies demonstrated that NF-α1/CPE exerted protective activity against oxidative stress in HEK293 cells by interacting with 5-HTR1E and activating downstream β-arrestin/ERK/CREB/BCL2 signaling cascade ( Sharma et al, 2021 ). Furthermore, studies showed that NFα1/CPE treatment decreased cytotoxicity induced by oxidative stress in primary human neurons, but not when HTR1E expression was knocked-out in these neurons ( Sharma et al, 2021 ).…”

Section: Role Of Neurotrophic Factor-α1/carboxypeptidase E and Its Re...mentioning

confidence: 99%

“…Cell biological studies demonstrated that NF-α1/CPE exerted protective activity against oxidative stress in HEK293 cells by interacting with 5-HTR1E and activating downstream β-arrestin/ERK/CREB/BCL2 signaling cascade ( Sharma et al, 2021 ). Furthermore, studies showed that NFα1/CPE treatment decreased cytotoxicity induced by oxidative stress in primary human neurons, but not when HTR1E expression was knocked-out in these neurons ( Sharma et al, 2021 ). These ex vivo studies indicated the physiological role of HTR1E-NFα1/CPE interaction in neuroprotection of human neurons.…”

Section: Role Of Neurotrophic Factor-α1/carboxypeptidase E and Its Re...mentioning

confidence: 99%

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Neurotrophic Factor-α1/Carboxypeptidase E Functions in Neuroprotection and Alleviates Depression

Xiao

Loh

2022

Front. Mol. Neurosci.

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Depression is a major psychiatric disease affecting all ages and is often co-morbid with neurodegeneration in the elderly. Depression and neurodegeneration are associated with decreased neurotrophic factors. In this mini-review the functions and potential therapeutic use of a newly discovered trophic factor, Neurotrophic factor-α1 (NF-α1), also known as Carboxypeptidase E (CPE), in depression and neuroprotection are discussed. NF-α1/CPE expression is enriched in CA3 neurons of the hippocampus. Families carrying null and homozygous non-sense mutations of the NF-α1/CPE gene share common clinical features including childhood onset obesity, type 2 diabetes, impaired intellectual abilities and hypogonadotrophic hypogonadism. Studies in animal models such as CPE knockout (KO) mice and CPEfat/fat mutant mice exhibit similar phenotypes. Analysis of CPE-KO mouse brain revealed that hippocampal CA3 was completely degenerated after weaning stress, along with deficits in hippocampal long-term potentiation. Carbamazepine effectively blocked weaning stress-induced hippocampal CA3 degeneration, suggesting the stress induced epileptic-like neuronal firing led to the degeneration. Analysis of possible mechanisms underlying NF-α1/CPE -mediated neuroprotection revealed that it interacts with the serotonin receptor, 5-HTR1E, and via β arrestin activation, subsequently upregulates ERK1/2 signaling and pro-survival protein, BCL2, levels. Furthermore, the NF-α1/CPE promoter contains a peroxisome proliferator-activated receptor (PPARγ) binding site which can be activated by rosiglitazone, a PPARγ agonist, to up-regulate expression of NF-α1/CPE and neurogenesis, resulting in anti-depression in animal models. Rosiglitazone, an anti-diabetic drug administered to diabetic patients resulted in decline of depression. Thus, NF-α1/CPE is a potential therapeutic agent or drug target for treating depression and neurodegenerative disorders.

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Novel interaction between neurotrophic factor-α1/carboxypeptidase E and serotonin receptor, 5-HTR1E, protects human neurons against oxidative/neuroexcitotoxic stress via β-arrestin/ERK signaling

Cited by 21 publications

References 48 publications

Exosomal Carboxypeptidase E (CPE) and CPE-shRNA-Loaded Exosomes Regulate Metastatic Phenotype of Tumor Cells

Exosomal Carboxypeptidase E (CPE) and CPE-shRNA-Loaded Exosomes Regulate Metastatic Phenotype of Tumor Cells

Explore the Mechanism of β-Asarone on Improving Cognitive Dysfunction in Rats with Diabetic Encephalopathy

Neurotrophic Factor-α1/Carboxypeptidase E Functions in Neuroprotection and Alleviates Depression

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