Int J Med Sci 2018; 15(7):674-681. doi:10.7150/ijms.23782 This issue Cite

Research Paper

Inhibition of CRL-NEDD8 pathway as a new approach to enhance ATRA-induced differentiation of acute promyelocytic leukemia cells

Shuyuan Liu#, Jinhua Wan#, Yunyuan Kong, Yonglu Zhang, Lagen Wan, Zhanglin Zhang

Department of Clinical laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
#These authors contributed equally to this work.

Citation:
Liu S, Wan J, Kong Y, Zhang Y, Wan L, Zhang Z. Inhibition of CRL-NEDD8 pathway as a new approach to enhance ATRA-induced differentiation of acute promyelocytic leukemia cells. Int J Med Sci 2018; 15(7):674-681. doi:10.7150/ijms.23782. https://www.medsci.org/v15p0674.htm
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Abstract

The cullin-RING ligase (CRL)-NEDD8 pathway maintains essential cellular processes, including cell cycle progression, apoptosis, autophagy, DNA repair, antigen processing and signal transduction. Growing evidence demonstrates that the alteration of the CRL-NEDD8 pathway in some cancers constitutes an attractive target for therapeutic intervention, but the roles of CRL-NEDD8 pathway in acute promyelocytic leukemia (APL) is still unclear. In the present study, we found that ATRA could decrease the expression of NEDD8-activating enzyme E1 (NAE1) and inhibit the neddylation of cullin1 and cullin3 in the APL cell line NB4. Inactivation of cullin neddylation promoted self-degradation of F-box proteins (Skp2, KLHL20, βTrCP) and up-regulated the protein expression of p27kip, DEPTOR and DAPK1. MLN4924, a novel inhibitor of NAE1, significantly suppressed cell growth and enhanced apoptosis of APL cells by blocking cullin neddylation and subsequent accumulation of CRL E3 substrates. Furthermore, MLN4924 effectively enhanced ATRA-induced differentiation of APL cells by promoting autophagy. Our findings not only provide further insights into the mechanism of the CRL-NEDD8 axis, but also provide a better understanding of this pathway as a potential target for therapeutic intervention in APL.

Keywords: ATRA, differentiation, CRL-NEDD8, MLN4924, neddylation


Citation styles

APA
Liu, S., Wan, J., Kong, Y., Zhang, Y., Wan, L., Zhang, Z. (2018). Inhibition of CRL-NEDD8 pathway as a new approach to enhance ATRA-induced differentiation of acute promyelocytic leukemia cells. International Journal of Medical Sciences, 15(7), 674-681. https://doi.org/10.7150/ijms.23782.

ACS
Liu, S.; Wan, J.; Kong, Y.; Zhang, Y.; Wan, L.; Zhang, Z. Inhibition of CRL-NEDD8 pathway as a new approach to enhance ATRA-induced differentiation of acute promyelocytic leukemia cells. Int. J. Med. Sci. 2018, 15 (7), 674-681. DOI: 10.7150/ijms.23782.

NLM
Liu S, Wan J, Kong Y, Zhang Y, Wan L, Zhang Z. Inhibition of CRL-NEDD8 pathway as a new approach to enhance ATRA-induced differentiation of acute promyelocytic leukemia cells. Int J Med Sci 2018; 15(7):674-681. doi:10.7150/ijms.23782. https://www.medsci.org/v15p0674.htm

CSE
Liu S, Wan J, Kong Y, Zhang Y, Wan L, Zhang Z. 2018. Inhibition of CRL-NEDD8 pathway as a new approach to enhance ATRA-induced differentiation of acute promyelocytic leukemia cells. Int J Med Sci. 15(7):674-681.

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