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Cell Death Dis. 2016 Dec 1;7(12):e2505. doi: 10.1038/cddis.2016.395.

Distinct outcomes of CRL-Nedd8 pathway inhibition reveal cancer cell plasticity.

Rulina AV1,2,3, Mittler F1,2,3, Obeid P1,2,3, Gerbaud S1,2,3, Guyon L1,2,3, Sulpice E1,2,3, Kermarrec F1,2,3, Assard N1,2,3, Dolega ME1,2,3, Gidrol X1,2,3, Balakirev MY1,2,3.

Author information

1
Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 Grenoble, France.
2
University Grenoble Alpes, BIG-BGE, F-38000 Grenoble, France.
3
INSERM, BGE, F-38000 Grenoble, France.

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.

PMID:
27906189
PMCID:
PMC5261022
DOI:
10.1038/cddis.2016.395
[Indexed for MEDLINE]
Free PMC Article

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