Targeting cullin-RING ligases for cancer treatment: rationales, advances and therapeutic implications

Abstract

New therapeutic intervention strategies for the treatment of human malignancies are always desired. Approval of bortezomib as a front-line treatment for multiple myeloma highlighted the significance of ubiquitin-proteasome system (UPS) as a promising therapeutic target. However, due to the broad impact of proteasome inhibition, deleterious side effects have been reported with bortezomib treatment. Cullin RING ligases (CRLs)-mediated ubiquitin conjugation process is responsible for the ubiquitin conjugation of 20 % cellular proteins that are designated for degradation through the UPS, most of them are critical proteins involved in cell cycle progression, signaling transduction and apoptosis. Studies have depicted the upstream NEDDylation pathway that controls the CRL activity by regulating the conjugation of an ubiquitin-like-protein NEDD8 to the cullin protein in the complex. A specific pharmaceutical inhibitor of NEDD8 activating enzyme (NAE; E1) MLN4924 was recently developed and has been promoted to Phase I clinical trials for the treatment of several human malignancies. This article summarizes the most recent understanding about the process of NEDD8 conjugation, its relevance for cancer therapy and molecular mechanisms responsible for the potent anti-tumor activity of MLN4924.

Keywords: DNA damage; MLN4924; NEDD8; NEDDylation; Ubiquitin; mTOR.

Fig. 1

Proposed cytotoxic mechanisms of NEDDylaton inhibition in human malignancies. With inhibition of NEDD8 conjugation pathway, certain critical CRL substrates will accumulate and will lead to cancer cell death. Major proteins identified to induce cell death include cell cycle licensing factor Cdt1; cyclin-dependent kinase inhibitor p21; a negative regulator of entry into mitosis WEE1; mTOR pathway inhibitor Deptor 1; NFκB pathway inhibitor IκB. Due to distinct cellular context, different mechanisms were proposed in different cancer cell lines tested with MLN4924