Loss of PRP4K drives anoikis resistance in part by dysregulation of epidermal growth factor receptor endosomal trafficking

D. P. Corkery, L. E. Clarke, S. Gebremeskel, J. Salsman, J. Pinder, C. Le Page, L. Meunier, Z. Xu, A. M. Mes-Masson, J. N. Berman, B. Johnston, G. Dellaire

Résultat de recherche: Articleexamen par les pairs

21 Citations (Scopus)

Résumé

Anoikis acts as a critical barrier to metastasis by inducing cell death upon cancer cell detachment from the extracellular matrix (ECM), thereby preventing tumor cell dissemination to secondary sites. The induction of anoikis requires the lysosomal-mediated downregulation of epidermal growth factor receptors (EGFRs) leading to termination of pro-survival signaling. In this study, we demonstrate that depletion of pre-mRNA splicing factor 4 kinase (PRP4K; also known as PRPF4B) causes dysregulation of EGFR trafficking and anoikis resistance. We also report a novel cytoplasmic localization of PRP4K at the late endosome, and demonstrate both nuclear and cytoplasmic localization in breast, lung and ovarian cancer tissue. Mechanistically, depletion of PRP4K leads to reduced EGFR degradation following cell detachment from the ECM and correlates with increased TrkB, vimentin and Zeb1 expression. As a result, PRP4K loss promotes sustained growth factor signaling and increased cellular resistance to anoikis in vitro and in a novel zebrafish xenotransplantation model of anoikis sensitivity, as well as increased metastasis in a mouse model of ovarian cancer. Thus, PRP4K may serve as a potential biomarker of anoikis sensitivity in ovarian and other epithelial cancers.

Langue d'origineEnglish
Pages (de-à)174-184
Nombre de pages11
JournalOncogene
Volume37
Numéro de publication2
DOI
Statut de publicationPublished - janv. 11 2018

Note bibliographique

Funding Information:
We thank the Gynecology-Oncology and Pathology services of the CHUM-Hôpital Notre-Dame for tumor procurement, Gretchen Wagner for fish care, and Monique Bernard for technical assistance. Ovarian and breast tumor banking was supported by the Cancer Research Network Tissue Bank of the Fonds de recherche du Québec— Santé (FRQS). This work was funded by research grants from the Canadian Breast Cancer Foundation (CBCF) and the Breast Cancer Society/QEII Foundation awarded to GD, and research grants to BJ from the Canadian Institutes of Health Research (CIHR) (MOP-110988, PJT-153285). GD, JB and BJ are Senior Scientists of the Beatrice Hunter Cancer Research Institute (BHCRI), and DPC, LC, JS and JP were supported by trainee awards from the BHCRI with funds provided by CBCF—Atlantic, The Canadian Cancer Society, Nova Scotia Division as part of The Terry Fox Foundation Strategic Health Research Training (STIHR) Program in Cancer Research at the CIHR. SG is the recipient of doctoral awards from the Killam Trusts, CIHR, and BHCRI.

ASJC Scopus Subject Areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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