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PML/RARα fusion protein mediates the unique sensitivity to arsenic cytotoxicity in acute promyelocytic leukemia cells: Mechanisms involve the impairment of cAMP signaling and the aberrant regulation of NADPH oxidase
Author(s) -
Li Lingna,
Wang Jie,
Ye Richard D.,
Shi Guiying,
Jin Huifang,
Tang Xueming,
Yi Jing
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21523
Subject(s) - arsenic trioxide , acute promyelocytic leukemia , u937 cell , nadph oxidase , microbiology and biotechnology , promyelocytic leukemia protein , biology , monocytic leukemia , reactive oxygen species , fusion protein , chemistry , cell culture , leukemia , cancer research , biochemistry , apoptosis , immunology , genetics , retinoic acid , recombinant dna , gene
Abstract Acute promyelocytic leukemia (APL) cells are characterized by PML/RARα fusion protein, high responsiveness to arsenic trioxide (ATO)‐induced cytotoxicity and an abundant generation of reactive oxygen species (ROS). In this study we investigated the association among these three features in APL‐derived NB4 cells. We found that NADPH oxidase‐derived ROS generation was more abundant in NB4 cells compared with monocytic leukemia U937 cells. By using PR9, a sub‐line of U937 stably transduced with the inducible PML/RARα expression vectors, we attributed disparities on ROS generation and ATO sensitivity to the occurrence of PML/RARα fusion protein, since PML/RARα‐expressing cells appeared higher NADPH oxidase activity, higher ROS level and higher sensitivity to ATO. On the other hand, the basal intensity of cAMP signaling pathway was compared between NB4 and U937 as well as between PR9 cells with or without PML/RARα, demonstrating that PML/RARα‐expressing cells had an impaired cAMP signaling pathway which relieved its inhibitory effect on NADPH oxidase derived ROS generation. In summary, the present study demonstrated the correlation of PML/RARα with cAMP signaling pathway, NADPH oxidase and ROS generation in APL cells. PML/RARα that bestows NB4 cells various pathological features, paradoxically also endows these cells with the basis for susceptibility to ATO‐induced cytotoxcity. J. Cell. Physiol. 217: 486–493, 2008. © 2008 Wiley‐Liss, Inc.