Small protein blockers of human IL-6 receptor alpha inhibit proliferation and migration of cancer cells

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F24%3A00586070" target="_blank" >RIV/61388971:_____/24:00586070 - isvavai.cz</a>

Alternative codes found

RIV/86652036:_____/24:00586070 RIV/61989592:15110/24:73627272 RIV/44555601:13440/24:43898632 RIV/00216208:11110/24:10482400 RIV/00098892:_____/24:10158624

Result on the web

<a href="https://biosignaling.biomedcentral.com/articles/10.1186/s12964-024-01630-w" target="_blank" >https://biosignaling.biomedcentral.com/articles/10.1186/s12964-024-01630-w</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s12964-024-01630-w" target="_blank" >10.1186/s12964-024-01630-w</a>

Result language

angličtina

Original language name

Small protein blockers of human IL-6 receptor alpha inhibit proliferation and migration of cancer cells

Original language description

Background Interleukin-6 (IL-6) is a multifunctional cytokine that controls the immune response, and its role has been described in the development of autoimmune diseases. Signaling via its cognate IL-6 receptor (IL-6R) complex is critical in tumor progression and, therefore, IL-6R represents an important therapeutic target.Methods An albumin-binding domain-derived highly complex combinatorial library was used to select IL-6R alpha (IL-6R alpha)-targeted small protein binders using ribosome display. Large-scale screening of bacterial lysates of individual clones was performed using ELISA, and their IL-6R alpha blocking potential was verified by competition ELISA. The binding of proteins to cells was monitored by flow cytometry and confocal microscopy on HEK293T-transfected cells, and inhibition of signaling function was examined using HEK-Blue IL-6 reporter cells. Protein binding kinetics to living cells was measured by LigandTracer, cell proliferation and toxicity by iCELLigence and Incucyte, cell migration by the scratch wound healing assay, and prediction of binding poses using molecular modeling by docking.Results We demonstrated a collection of protein variants called NEF ligands, selected from an albumin-binding domain scaffold-derived combinatorial library, and showed their binding specificity to human IL-6R alpha and antagonistic effect in HEK-Blue IL-6 reporter cells. The three most promising NEF108, NEF163, and NEF172 variants inhibited cell proliferation of malignant melanoma (G361 and A2058) and pancreatic (PaTu and MiaPaCa) cancer cells, and suppressed migration of malignant melanoma (A2058), pancreatic carcinoma (PaTu), and glioblastoma (GAMG) cells in vitro. The NEF binders also recognized maturation-induced IL-6R alpha expression and interfered with IL-6-induced differentiation in primary human B cells.Conclusion We report on the generation of small protein blockers of human IL-6R alpha using directed evolution. NEF proteins represent a promising class of non-toxic anti-tumor agents with migrastatic potential.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10601 - Cell biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cell communication and signaling : CCS

ISSN

1478-811X

e-ISSN

1478-811X

Volume of the periodical

22

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

26

Pages from-to

261

UT code for WoS article

001215466500002

EID of the result in the Scopus database

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