Distinct outcomes of CRL–Nedd8 pathway inhibition reveal cancer cell plasticity View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-12-01

AUTHORS

Anastasia V Rulina, Frédérique Mittler, Patricia Obeid, Sophie Gerbaud, Laurent Guyon, Eric Sulpice, Frédérique Kermarrec, Nicole Assard, Monika E Dolega, Xavier Gidrol, Maxim Y Balakirev

ABSTRACT

Inhibition of protein degradation by blocking Cullin-RING E3 ligases (CRLs) is a new approach in cancer therapy though of unknown risk because CRL inhibition may stabilize both oncoproteins and tumor suppressors. Probing CRLs in prostate cancer cells revealed a remarkable plasticity of cells with TMPRSS2-ERG translocation. CRL suppression by chemical inhibition or knockdown of RING component RBX1 led to reversible G0/G1 cell cycle arrest that prevented cell apoptosis. Conversely, complete blocking of CRLs at a higher inhibitor dose-induced cytotoxicity that was amplified by knockdown of CRL regulator Cand1. We analyzed cell signaling to understand how varying degrees of CRL inhibition translated to distinct cell fates. Both tumor suppressor and oncogenic cell signaling pathways and transcriptional activities were affected, with pro-metastatic Wnt/β-catenin as the most upregulated. Suppression of the NF-κB pathway contributed to anti-apoptotic effect, and androgen receptor (AR) and ERG played decisive, though opposite, roles: AR was involved in protective quiescence, whereas ERG promoted apoptosis. These data define AR–ERG interaction as a key plasticity and survival determinant in prostate cancer and suggest supplementary treatments that may overcome drug resistance mechanisms regulated by AR–ERG interaction. More... »

PAGES

e2505-e2505

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/cddis.2016.395

DOI

http://dx.doi.org/10.1038/cddis.2016.395

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1031204139

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27906189


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