Cullin-RING Ligases as Attractive Anti-cancer Targets

Abstract

The ubiquitin-proteasome system (UPS) promotes the timely degradation of short-lived proteins with key regulatory roles in a vast array of biological processes, such as cell cycle progression, oncogenesis and genome integrity. Thus, abnormal regulation of UPS disrupts the protein homeostasis and causes many human diseases, particularly cancer. Indeed, the FDA approval of bortezomib, the first class of general proteasome inhibitor, for the treatment of multiple myeloma, demonstrated that the UPS can be an attractive anti-cancer target. However, normal cell toxicity associated with bortezomib, resulting from global inhibition of protein degradation, promotes the focus of drug discovery efforts on targeting enzymes upstream of the proteasome for better specificity. E3 ubiquitin ligases, particularly those known to be activated in human cancer, become an attractive choice. Cullin-RING Ligases (CRLs) with multiple components are the largest family of E3 ubiquitin ligases and are responsible for ubiquitination of ~20% of cellular proteins degraded through UPS. Activity of CRLs is dynamically regulated and requires the RING component and cullin neddylation. In this review, we will introduce the UPS and CRL E3s and discuss the biological processes regulated by each of eight CRLs through substrate degradation. We will further discuss how cullin neddylation controls CRL activity, and how CRLs are being validated as the attractive cancer targets by abrogating the RING component through genetic means and by inhibiting cullin neddylation via MLN4924, a small molecule indirect inhibitor of CRLs, currently in several Phase I clinical trials. Finally, we will discuss current efforts and future perspectives on the development of additional inhibitors of CRLs by targeting E2 and/or E3 of cullin neddylation and CRL-mediated ubiquitination as potential anti-cancer agents.

Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function

“…Here, we provide evidence that IP6, with nanomolar potency, participates in CRL-CSN dynamics, particularly for CRL1/4A. The CRLs affect fundamental cellular processes such as cell growth/ death and are deregulated in diverse diseases, especially in cancer (3,36). Targeting IP5K/IP6 and its interface with CRL-CSN in combination therapy may alleviate the dose-limiting toxicity of MLN4924 observed in clinical trials (37).…”

Regulation of cancer-related pathways by protein NEDDylation and strategies for the use of NEDD8 inhibitors in the clinic

“…All cullins are modified with NEDD8, while modification of CUL7 is still controversial (Pan et al 2004, Skaar et al 2007. Cullins are scaffold proteins of multicomponent complexes named CRLs that control the stability of a rapidly growing list of proteins with diverse functions including cell cycle regulation, signalling, DNA repair, the response to hypoxia and oxidative stress, centrosome duplication cycle and cytoskeleton dynamics (Watson et al 2011, Zhao & Sun 2013. The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates.…”

CRL4A-FBXW5–mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth

“…degradation (24)(25)(26). The seven cullin proteins (CUL1, 2, 3, 4A, 4B, 5, and 7) can associate with a different family of substrate receptors, potentially forming as many as 300-500 distinct CRLs.…”