Epithelial-to-mesenchymal transition activates PERK-eIF2α and sensitizes cells to endoplasmic reticulum stress.

Autor:	Feng YX; Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts., Sokol ES; Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North CarolinaAuthors' Affiliations:Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina., Del Vecchio CA; Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina., Sanduja S; Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina., Claessen JH; Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina., Proia TA; Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina., Jin DX; Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North CarolinaAuthors' Affiliations:Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina., Reinhardt F; Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina., Ploegh HL; Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North CarolinaAuthors' Affiliations:Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina., Wang Q; Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North Carolina., Gupta PB; Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts; and Department of Chemistry, Duke University, Durham, North CarolinaAuthors' Affiliations:Whitehead Institute for Biomedical Research; Department of Biology, Massachusetts Institute of Technology; Koch Institute for Integrative Cancer Research; Harvard Stem Cell Institute; Broad Institute, Cambridge, Massachusetts pgupta@wi.mit.edu.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2014 Jun; Vol. 4 (6), pp. 702-15. Date of Electronic Publication: 2014 Apr 04.
DOI:	10.1158/2159-8290.CD-13-0945
Abstrakt:	Unlabelled: Epithelial-to-mesenchymal transition (EMT) promotes both tumor progression and drug resistance, yet few vulnerabilities of this state have been identified. Using selective small molecules as cellular probes, we show that induction of EMT greatly sensitizes cells to agents that perturb endoplasmic reticulum (ER) function. This sensitivity to ER perturbations is caused by the synthesis and secretion of large quantities of extracellular matrix (ECM) proteins by EMT cells. Consistent with their increased secretory output, EMT cells display a branched ER morphology and constitutively activate the PERK-eIF2α axis of the unfolded protein response (UPR). Protein kinase RNA-like ER kinase (PERK) activation is also required for EMT cells to invade and metastasize. In human tumor tissues, EMT gene expression correlates strongly with both ECM and PERK-eIF2α genes, but not with other branches of the UPR. Taken together, our findings identify a novel vulnerability of EMT cells, and demonstrate that the PERK branch of the UPR is required for their malignancy. Significance: EMT drives tumor metastasis and drug resistance, highlighting the need for therapies that target this malignant subpopulation. Our findings identify a previously unrecognized vulnerability of cancer cells that have undergone an EMT: sensitivity to ER stress. We also find that PERK-eIF2α signaling, which is required to maintain ER homeostasis, is also indispensable for EMT cells to invade and metastasize. (©2014 American Association for Cancer Research.)
Databáze:	MEDLINE
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