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Target spot for treating tumor, application of target spot and tumor treatment preparation

A preparation and tumor technology, applied in the field of anti-tumor drug development and treatment, can solve problems such as protein interaction and its biological significance that have not been reported.

Pending Publication Date: 2022-04-19
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Both CD38 and PRMT5 are potential tumor intervention targets, but the interaction between these two proteins and their biological significance have not been reported so far

Method used

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  • Target spot for treating tumor, application of target spot and tumor treatment preparation
  • Target spot for treating tumor, application of target spot and tumor treatment preparation
  • Target spot for treating tumor, application of target spot and tumor treatment preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] figure 1 A is the SDS-PAGE electrophoresis staining image of CD38 immunoprecipitation complex; cervical cancer CaSki cells stably expressing Flag-CD38 were cultured in 1640 medium containing 10% fetal bovine serum, cell extracts were prepared after 48 hours, and anti-Flag parent Use it with gel beads to precipitate Flag-CD38 and proteins that interact with CD38, and take an appropriate amount of protein as a positive control, and divide the remaining protein into two equal parts to incubate with IgG and Flag affinity gel beads, and then remove An appropriate amount of Western technology was used to identify whether Flag-CD38 was enriched. In order to identify and identify protein purification, the obtained protein was separated by SDS-acrylamide gel electrophoresis, and then decolorized after staining with Coomassie. It was found that an obvious difference band appeared at the 72kDa position. Western blot experiments showed that Flag-CD38 was successfully enriched.

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Embodiment 2

[0089] figure 2 A is the different truncated regions of CD38: as a transmembrane protein, CD38 is composed of intracellular domain, transmembrane domain and extracellular domain, so CD38 is divided into three segments, namely D1 (intracellular segment), D2 (transmembrane segment), D3 (extracellular segment), constructed as a vector with Flag and fused to express Flag. Transiently transfer the full length of Flag-CD38, Flag-D1, Flag-D2, and Flag-D3 into 293T cells, collect the cell lysate after 48 hours, and verify whether the construction of the three-segment domain is successful by using western blot experiments. The intracellular, transmembrane and extracellular domains of CD38 protein have been successfully constructed.

[0090] Full-length Flag-CD38: It represents the CD38 carrier with Flag, and the full-length amino acids of CD38 are as follows

[0091] MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTV...

Embodiment 3

[0105] image 3 A is western blot detection of CD38 protein levels after treatment with GSK591 (inhibiting PRMT5 methylation function): in CaSki, HNE2 cell lines, and A549 cells stably overexpressing CD38, using GSK591 (PRMT5 inhibitor) and DMSO treatment, found The protein level of CD38 was also significantly down-regulated after the methylation activity of PRMT5 was inhibited.

[0106] image 3 B is western blot detection of CD38 protein levels after treatment with different concentrations of GSK591 (inhibiting PRMT5 methylation function): In CaSki, HNE2 cell lines, and A549 cells stably overexpressing CD38, different concentrations of GSK591 (PRMT5 inhibitor) were used And DMSO treatment, the CD38 protein level decreased with the increase of GSK591 concentration, and the CD38 protein level decreased most obviously when the concentration was 500nM.

[0107] image 3 C is the detection of symmetrical arginine dimethylation of CD38 by co-immunoprecipitation technique: the f...

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Abstract

The invention discloses a target spot for treating tumors, application of the target spot and a tumor treatment preparation. A series of studies find that PRMT5 and CD38 in nasopharynx cancer, cervical cancer and lung cancer cells interact with each other, and PRMT5 enables CD38 protein to generate arginine methylation, so that the self enzyme activity of CD38 is influenced. Particularly, the 58th amino acid of the CD38 protein is subjected to arginine methylation. In-vivo and in-vitro experiments prove that the 58th arginine of the CD38 protein is changed into a glycine mutant which enters tumor cells, so that PRMT5 cannot enable the 58th arginine of the CD38 protein to be methylated and inhibit the self enzyme activity of the CD38, and further the proliferation and in-vivo tumorigenicity of the tumor cells are promoted by influencing an NAD-SIRT1-p53 axis, so that the effect of treating tumors is achieved. The anti-tumor CD38 is obvious in fixed-point target effect and free of obvious toxic and side effects.

Description

technical field [0001] The invention belongs to the technical field of research and development and treatment of anti-tumor drugs, and in particular relates to an anti-tumor target located on the CD38 protein, its application and a tumor treatment preparation. Background technique [0002] CD38 is a membrane-localized single-chain transmembrane glycoprotein, a multifunctional membrane molecule. CD38 is a marker molecule of T cell activation; it can act as a receptor molecule and combine with its ligand or monoclonal antibody to produce a variety of biological effects; it has the characteristics of an adhesion molecule and plays a certain role in lymphocyte recirculation and lymphocyte homing. The role of mediating transmembrane signal transmission. CD38 was initially considered as a reliable biomarker molecule for the diagnosis and prognosis of myeloma and chronic lymphocytic leukemia (CLL). FDA has approved two CD38 antibodies (Daratumumab and Isatuximab) for the treatment...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61P35/00C07K14/705G01N33/574G01N33/68
CPCA61K45/00A61P35/00C07K14/70596G01N33/6845G01N33/6872G01N33/6893G01N33/57423G01N33/57411G01N33/57407
Inventor 周艳宏梁琳曾凤李欣高梦祥李文涛金曦贺军宇贺正希李艳玲
Owner CENT SOUTH UNIV
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