Blocking lipid raft-associated RANK/c-Src signaling inhibits TRAF6-mediated non-small cell lung cancer migration.

Authors

Danfei Zhou, Jun Ying, Haijian Liu, Shanshan Hu, Jiangdong Li, Jiaojiao Ren

Published in

Biochimica et biophysica acta. General subjects. Pages 131006. Sep 23, 2026. Epub Sep 23, 2026.

Abstract

Lipid rafts, cholesterol- and glycosphingolipid-rich membrane platforms with stimuli-transducing molecules, facilitate cancer cell migration via aggregation. TNF receptor associated factor 6 (TRAF6), a known oncogene in lung cancer, interacts with receptor activator of nuclear factor-kB (RANK) (localized on lipid rafts) and Cellular (c)-Src (a lipid raft component), leading us to hypothesize that blocking lipid raft-localized RANK/c-Src may attenuate TRAF6-driven tumor progression.
Following transfection with TRAF6 overexpression plasmid, transfection efficiency was verified by western blot. Subsequently, A549 cells were treated with Nystatin (a lipid raft/Caveolin-1 inhibitor) or PP2 (a c-Src inhibitor). Cell viability, migration and apoptosis were evaluated using CCK-8 assay, wound healing assay and flow cytometry, respectively. Lipid raft aggregation was observed via immunofluorescence microscopy, while the expression levels of TRAF6, RANK, c-Src, Clathrin and Caveolin-1 in lipid rafts were detected by electrophoresis combined with western blot.
TRAF6 overexpression significantly enhanced the viability and migration of NSCLC cells, while suppressing apoptosis. Furthermore, TRAF6 upregulation effectively induced lipid raft aggregation and elevated the expression levels of Caveolin-1, RANK, and c-Src within lipid raft domains. Notably, treatment with either Nystatin or PP2 markedly counteracted the aforementioned pro-tumorigenic effects of TRAF6, including the restoration of apoptotic rates, inhibition of cell migration and viability, inhibition of lipid raft aggregation and decreased expression of key molecules in lipid raft fractions.
Blocking the lipid raft-localized RANK/c-Src pathway reverses TRAF6-mediated pro-tumor effects in NSCLC in vitro, providing novel insights into the mechanism by which TRAF6 regulates NSCLC progression.

PMID:
42777925
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

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