PLoS ONE (Jan 2017)

The anti-tumorigenic activity of A2M-A lesson from the naked mole-rat.

  • Susanne Kurz,
  • René Thieme,
  • Ronny Amberg,
  • Marco Groth,
  • Heinz-Georg Jahnke,
  • Philipp Pieroh,
  • Lars-Christian Horn,
  • Marlen Kolb,
  • Klaus Huse,
  • Matthias Platzer,
  • Daniela Volke,
  • Faramarz Dehghani,
  • Anton Buzdin,
  • Kathrin Engel,
  • Andrea Robitzki,
  • Ralf Hoffmann,
  • Ines Gockel,
  • Gerd Birkenmeier

DOI
https://doi.org/10.1371/journal.pone.0189514
Journal volume & issue
Vol. 12, no. 12
p. e0189514

Abstract

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Cancer resistance is a major cause for longevity of the naked mole-rat. Recent liver transcriptome analysis in this animal compared to wild-derived mice revealed higher expression of alpha2-macroglobulin (A2M) and cell adhesion molecules, which contribute to the naked mole-rat's cancer resistance. Notably, A2M is known to dramatically decrease with age in humans. We hypothesize that this might facilitate tumour development. Here we found that A2M modulates tumour cell adhesion, migration and growth by inhibition of tumour promoting signalling pathways, e.g. PI3K / AKT, SMAD and up-regulated PTEN via down-regulation of miR-21, in vitro and in tumour xenografts. A2M increases the expression of CD29 and CD44 but did not evoke EMT. Transcriptome analysis of A2M-treated tumour cells, xenografts and mouse liver demonstrated a multifaceted regulation of tumour promoting signalling pathways indicating a less tumorigenic environment mediated by A2M. By virtue of these multiple actions the naturally occurring A2M has strong potential as a novel therapeutic agent.