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

PLoS One. 2017 Dec 27;12(12):e0189514. doi: 10.1371/journal.pone.0189514. eCollection 2017.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Heterografts
  • Humans
  • Models, Animal
  • Mole Rats
  • Neoplasms / pathology
  • Neoplasms / prevention & control*
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Pregnancy-Associated alpha 2-Macroglobulins / physiology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Smad Proteins / metabolism


  • Pregnancy-Associated alpha 2-Macroglobulins
  • Smad Proteins
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase

Grant support

This work was supported by Europäischer Sozialfond-ESF (100098250). We acknowledge support from the German Research Foundation (DFG) and Leipzig University within the program of Open Access Publishing.