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JS‐K, a novel non‐ionic diazeniumdiolate derivative, inhibits Hep 3B hepatoma cell growth and induces c‐Jun phosphorylation via multiple MAP kinase pathways
Author(s) -
Ren Zhenggang,
Kar Siddhartha,
Wang Ziqiu,
Wang Meifang,
Saavedra Joseph E.,
Carr Brian I.
Publication year - 2003
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.10380
Subject(s) - mapk/erk pathway , kinase , chemistry , inhibitory postsynaptic potential , protein kinase a , mitogen activated protein kinase , p38 mitogen activated protein kinases , cell growth , microbiology and biotechnology , phosphorylation , biochemistry , biology , endocrinology
JS‐K, a non‐ionic diazeniumdiolate derivative, is capable of arylating nucleophiles and spontaneously generating nitric oxide (NO) at physiological pH. This recently synthesized low molecular weight compound is shown here to be an inhibitor of cell growth with concomitant activation of mitogen‐activated protein kinase (MAPK) members ERK, JNK, and p38 and their downstream effectors c‐Jun and AP‐1. Inhibitors of these MAPK pathways abrogated the growth inhibitory actions of JS‐K. In addition to the well‐described actions of JNK as a kinase for c‐Jun, we show that c‐Jun is also an ERK target. Furthermore, JS‐K generated NO in culture and NO inhibitors antagonized both MAPK induction and the growth inhibitory effects of JS‐K. These results suggest two possible mechanisms for the mediation of JS‐K growth inhibitory actions, namely NO‐induction of MAPK pathway constituents as well as possible arylation reactions. The data support the idea that prolonged MAPK activation by JS‐K action is important in mediating its growth‐inhibitory actions. JS‐K thus represents a promising platform for novel growth inhibitory analog synthesis. J. Cell. Physiol. 197: 426–434, 2003© 2003 Wiley‐Liss, Inc.