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The p75^NTR and its carboxyl-terminal fragment exert opposing effects on melanoma cell proliferation and apoptosis via modulation of the NF-?B pathway.

ABSTRACT: The p75 neurotrophin receptor (p75^NTR ), a member of the tumor necrosis factor superfamily of receptors, is sensitive to proteolysis and has been observed to be expressed in various cancers. However, the roles of p75^NTR and its proteolytic fragments in tumorigenesis remain incompletely understood. Here, we report that the proportion of the p75^NTR carboxyl-terminal fragment (p75^NTR -CTF) is much higher than that of the full-length p75^NTR (p75^NTR -FL) in melanoma cells. Whereas p75^NTR -FL positively regulates apoptosis, p75^NTR -CTF promotes cell proliferation and survival, as well as increasing sorafenib resistance in vivo and in vitro. Moreover, p75^NTR -CTF activates the nuclear factor kappa B pathway and enhances the mRNA and protein levels of its downstream genes c-IAP1/2, FLIP, bFGF, IL8 and VEGF. On the contrary, p75^NTR -FL inhibits these processes. Taken together, these findings demonstrate that p75^NTR -CTF and p75^NTR -FL have opposing functions in melanoma cells, suggesting that the ratio of the two proteins affects the balance between cell death and survival. The presence of distinct p75^NTR proteolytic fragments may affect biological outcomes in tumor cells.

SUBMITTER: Zhong M

PROVIDER: S-EPMC7780107 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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The p75NTR and its carboxyl-terminal fragment exert opposing effects on melanoma cell proliferation and apoptosis via modulation of the NF-κB pathway.

Zhong Maojiao M Wang Yingying Y Muhammad Farrukh Nisar FN Gao Jing J Bian Chunxiang C

FEBS open bio 20201216 1

The p75 neurotrophin receptor (p75NTR ), a member of the tumor necrosis factor superfamily of receptors, is sensitive to proteolysis and has been observed to be expressed in various cancers. However, the roles of p75NTR and its proteolytic fragments in tumorigenesis remain incompletely understood. Here, we report that the proportion of the p75NTR carboxyl-terminal fragment (p75NTR -CTF) is much higher than that of the full-length p75NTR (p75 ...[more]

PMID: 33247998

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Project description:Mesenchymal stem cells (MSCs) are a promising therapy to improve vascular repair, yet their role in ischemic retinopathy is not fully understood. The aim of this study is to investigate the impact of modulating the neurotrophin receptor; p75NTR on the vascular protection of MSCs in an acute model of retinal ischemia/reperfusion (I/R). Wild type (WT) and p75NTR-/- mice were subjected to I/R injury by increasing intra-ocular pressure to 120 mmHg for 45 min, followed by perfusion. Murine GFP-labeled MSCs (100,000 cells/eye) were injected intravitreally 2 days post-I/R and vascular homing was assessed 1 week later. Acellular capillaries were counted using trypsin digest 10-days post-I/R. In vitro, MSC-p75NTR was modulated either genetically using siRNA or pharmacologically using the p75NTR modulator; LM11A-31, and conditioned media were co-cultured with human retinal endothelial cells (HREs) to examine the angiogenic response. Finally, visual function in mice undergoing retinal I/R and receiving LM11A-31 was assessed by visual-clue water-maze test. I/R significantly increased the number of acellular capillaries (3.2-Fold) in WT retinas, which was partially ameliorated in p75NTR-/- retinas. GFP-MSCs were successfully incorporated and engrafted into retinal vasculature 1 week post injection and normalized the number of acellular capillaries in p75NTR-/- retinas, yet ischemic WT retinas maintained a 2-Fold increase. Silencing p75NTR on GFP-MSCs coincided with a higher number of cells homing to the ischemic WT retinal vasculature and normalized the number of acellular capillaries when compared to ischemic WT retinas receiving scrambled-GFP-MSCs. In vitro, silencing p75NTR-MSCs enhanced their secretome, as evidenced by significant increases in SDF-1, VEGF and NGF release in MSCs conditioned medium; improved paracrine angiogenic response in HREs, where HREs showed enhanced migration (1.4-Fold) and tube formation (2-Fold) compared to controls. In parallel, modulating MSCs-p75NTR using LM11A-31 resulted in a similar improvement in MSCs secretome and the enhanced paracrine angiogenic potential of HREs. Further, intervention with LM11A-31 significantly mitigated the decline in visual acuity post retinal I/R injury. In conclusion, p75NTR modulation can potentiate the therapeutic potential of MSCs to harness vascular repair in ischemic retinopathy diseases.

Dataset Information

The p75^NTR and its carboxyl-terminal fragment exert opposing effects on melanoma cell proliferation and apoptosis via modulation of the NF-?B pathway.

Publications

The p75<sup>NTR</sup> and its carboxyl-terminal fragment exert opposing effects on melanoma cell proliferation and apoptosis via modulation of the NF-κB pathway.

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Dataset Information

The p75NTR and its carboxyl-terminal fragment exert opposing effects on melanoma cell proliferation and apoptosis via modulation of the NF-?B pathway.

Publications

The p75<sup>NTR</sup> and its carboxyl-terminal fragment exert opposing effects on melanoma cell proliferation and apoptosis via modulation of the NF-κB pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The p75^NTR and its carboxyl-terminal fragment exert opposing effects on melanoma cell proliferation and apoptosis via modulation of the NF-?B pathway.