Impairment of Cell Adhesion and Migration by Inhibition of Protein Disulphide Isomerases in Three Breast Cancer Cell Lines

Harry S Young, Lucy M McGowan, Katy A Jepson, Josephine C Adams*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

Abstract

Protein disulphide isomerase A3 (PDIA3) is an ER-resident disulphide isomerase and oxidoreductase with known substrates that include some extracellular matrix proteins. PDIA3 is upregulated in invasive breast cancers and correlates in a mouse orthotopic xenograft model with breast cancer metastasis to bone. However, the underlying cellular mechanisms remain unclear. Here we investigated the function of protein disulphide isomerases in attachment, spreading and migration of three human breast cancer lines representative of luminal (MCF-7) or basal (MDA-MB-231 and HCC1937) tumour phenotypes. Pharmacological inhibition by 16F16 in cells decreased initial cell spreading more effectively than inhibition by PACMA-31. Cells displayed diminished cortical F-actin projections, stress fibres and focal adhesions. Cell migration was reduced in a quantified “scratch wound” assay. To examine whether these effects might result from alterations to secreted proteins in the absence of functional PDIA3, adhesion and migration were quantified in the above cells exposed to media conditioned by wild-type or Pdia3-/- mouse embryo fibroblasts. The conditioned medium of Pdia3-/- fibroblasts was less effective in promoting cell spreading and F-actin organisation or supporting “scratch wound” closure. Similarly, extracellular matrix prepared from HCC1937 cells after 16F16 inhibition was less effective than control ECM to support spreading of untreated HCC1937 cells. Overall, these results advance the concept that protein disulphide isomerases including PDIA3 drive the production of secreted proteins that promote a microenvironment favourable to breast cancer cell adhesion and motility, characteristics that are integral to tumour invasion and metastasis. Inhibition of PDIA3 or related isomerases may have potential for anti-metastatic therapies.
Original languageEnglish
JournalBioscience Reports
DOIs
Publication statusPublished - 14 Oct 2020

Keywords

  • Breast cancer
  • Cell migration
  • Cell attachment
  • ERp57/PDIA3
  • Protein disulfide isomerase A1
  • Secretome

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