Secretion of extracellular hsp90α via exosomes increases cancer cell motility: A role for plasminogen activation

  • McCready J
  • Sims J
  • Chan D
 et al. 
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Abstract

BACKGROUND: Metastasis is a multi-step process that is responsible for the majority of deaths in cancer patients. Current treatments are not effective in targeting metastasis. The molecular chaperone hsp90alpha is secreted from invasive cancer cells and activates MMP-2 to enhance invasiveness, required for the first step in metastasis. METHODS: We analyzed the morphology and motility of invasive cancer cells that were treated with exogenous exosomes in the presence or absence of hsp90alpha. We performed mass spectrometry and immunoprecipitation to identify plasminogen as a potential client protein of extracellular hsp90alpha. Plasmin activation assays and migration assays were performed to test if plasminogen is activated by extracellular hsp90alpha and has a role in migration. RESULTS: We found that hsp90alpha is secreted in exosomes in invasive cancer cells and it contributes to their invasive nature. We identified a novel interaction between hsp90alpha and tissue plasminogen activator that together with annexin II, also found in exosomes, activates plasmin. Extracellular hsp90alpha promotes plasmin activation as well as increases plasmin dependent cell motility. CONCLUSIONS: Our data indicate that hsp90alpha is released by invasive cancer cells via exosomes and implicates hsp90alpha in activating plasmin, a second protease that acts in cancer cell invasion.

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Authors

  • Jessica McCready

  • Jessica D. Sims

  • Doug Chan

  • Daniel G. Jay

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