Related Experiment Video
Updated: Mar 11, 2026
Impedance-based Real-time Measurement of Cancer Cell Migration and Invasion
Published on: April 2, 2020
Distinct outcomes of CRL-Nedd8 pathway inhibition reveal cancer cell plasticity
Anastasia V Rulina1,2,3, Frédérique Mittler1,2,3, Patricia Obeid1,2,3
1Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Institut Biosciences and Biotechnology-Grenoble (BIG) BGE-BIOMICS, F-38054 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.
Insights
Targeting protein degradation via Cullin-RING E3 ligases (CRLs) in prostate cancer shows dual effects. Low inhibition causes cell cycle arrest, while high inhibition induces cytotoxicity, influenced by androgen receptor (AR) and ERG interactions.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cullin-RING E3 ligases (CRLs) regulate protein degradation, presenting a novel cancer therapy target.
- CRL inhibition's impact on cancer cells, particularly regarding oncoprotein and tumor suppressor stability, remains unclear.
- Prostate cancer cells with TMPRSS2-ERG translocation exhibit plasticity under CRL modulation.
Purpose of the Study:
- To investigate the effects of varying degrees of CRL inhibition on prostate cancer cell fate.
- To elucidate the underlying cell signaling mechanisms and transcriptional changes associated with distinct cellular responses to CRL inhibition.
- To define the roles of androgen receptor (AR) and ERG in mediating cell plasticity and survival under CRL suppression.
Main Methods:
- Chemical inhibition and RBX1 knockdown were used to suppress CRL activity.
- Cand1 knockdown was employed to further block CRLs at higher inhibitor doses.
- Cell signaling pathways and transcriptional activities were analyzed to understand differential cell fates.
- The roles of AR and ERG in response to CRL inhibition were assessed.
Main Results:
- Partial CRL suppression induced reversible G0/G1 cell cycle arrest, preventing apoptosis.
- Complete CRL blockade, especially with Cand1 knockdown, resulted in amplified cytotoxicity.
- Upregulation of pro-metastatic Wnt/β-catenin signaling and suppression of the NF-κB pathway were observed.
- AR mediated protective quiescence, while ERG promoted apoptosis, with their interaction being crucial.
Conclusions:
- AR-ERG interaction is a critical determinant of plasticity and survival in prostate cancer.
- Varying degrees of CRL inhibition lead to distinct cell fates, highlighting a complex therapeutic window.
- Targeting AR-ERG pathways may offer strategies to overcome drug resistance in prostate cancer.
More Related Videos
Related Concept Videos
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
03:14Notch Signaling Pathway
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
02:56Treatment Resistant Cancers
02:34Inhibition of Cdk Activity