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Inhibition of all‐ Trans ‐retinoic acid‐induced proteasome activation potentiates the differentiating effect of retinoid in acute myeloid leukemia cells
Author(s) -
Fang Yanfen,
Zhou Xinglu,
Lin Meihua,
Ying Meidan,
Luo Peihua,
Zhu Difeng,
Lou Jianshu,
Yang Bo,
He Qiaojun
Publication year - 2011
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20687
Subject(s) - proteasome , retinoic acid , myeloid leukemia , biology , tretinoin , ubiquitin , leukemia , retinoid , downregulation and upregulation , cancer research , retinoic acid receptor , microbiology and biotechnology , cellular differentiation , acute promyelocytic leukemia , biochemistry , immunology , gene
All‐ trans retinoic acid (ATRA) is nowadays considered to be the sole efficient agent for differentiation‐based therapy in leukemia; however, the mechanisms of ATRA's biological effects remain largely unknown. Here we first reported that ATRA‐induced myeloid leukemia differentiation was accompanied with the increased level of ubiquitin–protein conjugates and the upregulation of proteasome activity. To explore the functional role of the activated proteasome in retinoic acid (RA) signaling, the effects of proteasome inhibitors on RA‐induced cell differentiation were determined. Our results demonstrated that inhibition of ATRA‐elevated proteasome activity obviously promoted the myeloid maturation program triggered by ATRA, suggesting that the overactivated proteasome is not beneficial for ATRA's effects. Further studies demonstrated that the synergistic differentiating effects of ATRA and proteasome inhibitors might be associated with the protection of retinoic acid receptor alpha (RARα) from degradation by the ubiquitin–proteasome pathway (UPP). Moreover, the accumulated RARα was able to enhance the transcription of its target gene, which might also contribute to the enhanced differentiation of leukemia cells. Together, by linking the UPP to ATRA‐dependent signaling, our data provide a novel insight into studying the mechanisms of ATRA‐elicited cellular effects and imply the possibility of combination of ATRA and proteasome inhibitors in leukemia therapy. Mol. Carcinog. © 2010 Wiley‐Liss, Inc.