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.

The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death

“…CRLs and NAE are often particularly active in cancer cells and promote growth, survival and invasion of tumor cells. In line with this, in vitro and in vivo studies revealed anti-tumoral activity of MLN4924 in a variety of cancer models and several clinical phase I studies indicate that MLN4924 is well tolerable 17,18 . At the molecular level, the anti-tumoral effects of MLN4924 have been traced back to the inhibition of the proteasomal degradation of various negative regulators of the DNA damage response, the cell cycle and senescence 17 .…”

Tunable protein synthesis by transcript isoforms in human cells

“…Indeed, in Caenorhabditis elegans , 3′ UTRs are sufficient to specify germline-specific expression of the attached ORF ( Merritt et al, 2008 ). Even without engineering of unnatural mRNAs, it may be possible to use antisense oligonucleotides to direct splicing of poorly- or well-translated isoforms to adjust protein expression in situ ( Kole et al, 2012 ), for example to downregulate the oncogenic NAE1 gene [ Figure 5A , Xie et al, 2014 ]), which is currently being targeted by small molecules ( Luo et al, 2012 ; Wu and Yu, 2015 ). We anticipate the ability to tune the translational output of mRNA will facilitate research and therapeutic uses of designed and endogenous mRNA molecules.…”

Exosomal Micro RNAs Derived from Dermal Papilla Cells Mediate Hair Follicle Stem Cell Proliferation and Differentiation

“…The HFSCs isolated from the HFs of Shaanbei White cashmere goat adults were identified, preserved, and cultured as previously described 23. Skin samples (1 cm 2 ) were clipped from the back of adult Shaanbei White cashmere goats, sterilized in 3% povidone iodine and 75% ethanol, cut into 0.5 cm × 0.5 cm segments using ophthalmic scissors, washed at least three times with phosphate-buffered saline (PBS), and then treated with 0.25% Dispase II for 14 h at 4 ºC.…”