title: Distinct outcomes of CRL-Nedd8 pathway inhibition reveal cancer cell plasticity.
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.
authors.affiliation: Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 Grenoble, France.|University Grenoble Alpes, BIG-BGE, F-38000 Grenoble, France.|INSERM, BGE, F-38000 Grenoble, France.
authors.forename: Anastasia V
authors.initials: AV
authors.lastname: Rulina
authors.affiliation: Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 Grenoble, France.|University Grenoble Alpes, BIG-BGE, F-38000 Grenoble, France.|INSERM, BGE, F-38000 Grenoble, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Mittler
authors.affiliation: Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 Grenoble, France.|University Grenoble Alpes, BIG-BGE, F-38000 Grenoble, France.|INSERM, BGE, F-38000 Grenoble, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Obeid
authors.affiliation: Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 Grenoble, France.|University Grenoble Alpes, BIG-BGE, F-38000 Grenoble, France.|INSERM, BGE, F-38000 Grenoble, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gerbaud
authors.affiliation: Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 Grenoble, France.|University Grenoble Alpes, BIG-BGE, F-38000 Grenoble, France.|INSERM, BGE, F-38000 Grenoble, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Guyon
authors.affiliation: Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 Grenoble, France.|University Grenoble Alpes, BIG-BGE, F-38000 Grenoble, France.|INSERM, BGE, F-38000 Grenoble, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Sulpice
authors.affiliation: Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 Grenoble, France.|University Grenoble Alpes, BIG-BGE, F-38000 Grenoble, France.|INSERM, BGE, F-38000 Grenoble, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Kermarrec
authors.affiliation: Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 Grenoble, France.|University Grenoble Alpes, BIG-BGE, F-38000 Grenoble, France.|INSERM, BGE, F-38000 Grenoble, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Assard
authors.affiliation: Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 Grenoble, France.|University Grenoble Alpes, BIG-BGE, F-38000 Grenoble, France.|INSERM, BGE, F-38000 Grenoble, France.
authors.forename: Monika E
authors.initials: ME
authors.lastname: Dolega
authors.affiliation: Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 Grenoble, France.|University Grenoble Alpes, BIG-BGE, F-38000 Grenoble, France.|INSERM, BGE, F-38000 Grenoble, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Gidrol
authors.affiliation: Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 Grenoble, France.|University Grenoble Alpes, BIG-BGE, F-38000 Grenoble, France.|INSERM, BGE, F-38000 Grenoble, France.
authors.forename: Maxim Y
authors.initials: MY
authors.lastname: Balakirev
mesh_terms: D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects; D000066670:Cell Plasticity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008954:Models, Biological; D000075687:NEDD8 Protein; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D000071230:Transcriptional Regulator ERG / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D003517:Cyclopentanes; C072312:ERG protein, human; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D011944:Receptors, Androgen; D000071230:Transcriptional Regulator ERG; D014452:Ubiquitins; C584471:CULL-RING ligase, human; D044767:Ubiquitin-Protein Ligases; C539933:pevonedistat