The actin filament cross-linker L-plastin confers resistance to TNF-alpha in MCF-7 breast cancer cells in a phosphorylation-dependent manner.

  • Tumor Microenvironment
  • Genomics Center
June 01, 2010 By:
  • Janji B
  • Vallar L
  • Al-Tanoury Z
  • Bernardin F
  • Vetter G
  • Schaffner-Reckinger E
  • Berchem G
  • Friederich E
  • Chouaib S.

Abstract We used a TNF-resistant breast adenocarcinoma MCF-7 cell line to investigate the involvement of the actin cytoskeleton in the mechanism of cell resistance to this cytokine. We found that TNF-resistance correlates with the loss of cell epithelial properties and the gain of a mesenchymal phenotype, reminiscent of an epithelial-to-mesenchymal transition (EMT). Morphological changes were associated with a profound reorganization of the actin cytoskeleton and with a change in the repertoire of expressed actin cytoskeleton genes and EMT markers, as revealed by DNA microarray-based expression profiling. L-plastin, an F-actin cross-linking and stabilizing protein, was identified as one of the most significantly up-regulated genes in TNF-resistant cells. Knock-down of L-plastin in these cells revealed its crucial role in conferring TNF-resistance. Importantly, overexpression of wild type L-plastin in TNF-sensitive MCF-7 cells was sufficient to protect them against TNF-mediated cell death. Furthermore, we found that this effect is dependent on serine-5 phosphorylation of L-plastin and that non-conventional PKC isoforms and the ceramide pathway may regulate its phosphorylation state. The protective role of L-plastin was not restricted to TNF-alpha resistant MCF-7 cells since a correlation between the expression of L-plastin and the resistance to TNF-alpha was observed in other breast cancer cell lines. Together, our study discloses a novel unexpected role of the actin bundling protein L-plastin as a cell protective protein against TNF-cytotoxicity.

2010 Jun. J Cell Mol Med.14(6A):1264-75. Epub 2009 Oct 3.
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