Yi Sun

Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA

Abstract:

Cullin-RING ligases (CRLs) are the largest family of E3 ubiquitin ligases. By promoting ubiqui-tination and degradation of a variety of key substrates, CRLs control many important biological processes including cell cycle progression, DNA repair, signal transduction, gene transcription, embryonic development, genomic integrity and tumorigenesis. CRLs, particularly its founding member, SCF (Skp1-Cullin-F-box proteins) E3 ligases are abnormally activated in a number of human cancers and have been validated as promising cancer targets [1]. MLN4924 is a newly discovered investigational small molecule inhibitor of NEDD8-Activating Enzyme (NAE) [2]. MLN4924 binds to NAE to create a covalent NEDD8-MLN4924 adduct, which cannot be further utilized in subsequent intraenzyme reactions, thus blocking NAE enzymatic activity [3]. Thus, by blocking cullin neddylation, MLN4924 inactivates CRLs and causes accumulation of CRLs substrates to suppress tumor cell growth both in vitro and in vivo. With promising preclinical efficacy, MLN4924 has been advanced to several Phase I clinical trials against a number of human malignancies [4, 5]. Our recent studies revealed that MLN4924 sensitizes leukemia cells to retinoid acid treatment by inducing apoptosis [6], and suppresses tumor cell growth by inducing senescence [7] and autophagy [8]. We also found that MLN4924 sensitizes otherwise resistant cancer cells of breast, lung and pancreas to radiation [9, 10]. In this presentation, we will discuss molecular mechanisms by which MLN4924 suppresses tumor growth. We will also discuss a potential advantage of MLN4924 over bortezomib, the first and only FDA approved general proteasome inhibitor for the treatment of multiple myeloma, given the fact that MLN4924 selectively inhibits degradation of a specific set of cellular proteins regulated by CRLs, whereas bortezomib blocks degradation of all proteins through the 26S proteasome with greater general cytotoxicity.

REFERENCES

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[2] Soucy, T.A., et al., An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 2009; 458(7239): p. 732-6.

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[6] Tan, M., et al., Inactivation of SAG E3 Ubiquitin Ligase Blocks Embryonic Stem Cell Differentiation and Sensitizes Leukemia Cells to Retinoid Acid. PLoS One 2011; 6(11): p. e27726.

[7] Jia, L., H. Li, and Y. Sun, Induction of p21-Dependent Senescence by an NAE Inhibitor, MLN4924, as a Mechanism of Growth Suppression. Neoplasia 2011; 13(6): p. 561-9.

[8] Zhao, Y., Xiong, X., Jia, L., and Sun, Y., Targeting cullin-RING ligases by MLN4924 induces autophagy via modulating the HIF1-REDD1-TSC1-mTORC1-DEPTOR axis. Cell Death Disease 2012; 3(e386): p. doi:10.1038/cddis.2012.125.

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[10] Yang, D., et al., The p21-Dependent Radiosensitization of Human Breast Cancer Cells by MLN4924, an Investigational Inhibitor of NEDD8 Activating Enzyme. PLoS One 2012; 7(3): p. e34079.