Inhibiting JNK Dephosphorylation and Induction of Apoptosis by Novel Anticancer Agent NSC-741909 in Cancer Cells

Department of Thoracic and Cardiovascular Surgery, University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
Journal of Biological Chemistry (Impact Factor: 4.6). 06/2009; 284(25):16948-55. DOI: 10.1074/jbc.M109.010256
Source: PubMed

ABSTRACT NSC-741909 is a recently identified novel anticancer agent that suppresses the growth of several NCI-60 cancer cell lines with a unique anticancer spectrum. However, its molecular mechanisms remain unknown. To determine the molecular mechanisms of NSC-741909-induced antitumor activity, we analyzed the changes of 77 protein biomarkers in a sensitive lung cancer cell line after treatment with this compound by using reverse-phase protein microarray. The results showed that phosphorylation of mitogen-activated protein (MAP) kinases (P38 MAPK, ERK, and JNK) were persistently elevated by the treatment with NSC-741909. However, only the JNK-specific inhibitor SP600125 effectively blocked the apoptosis induced by NSC-741909. Moreover, NSC-741909-mediated apoptosis was also blocked by a dominant-negative JNK construct, suggesting that sustained activation of JNK is critical for the apoptosis induction. Further studies revealed that treatment with NSC-741909 suppressed dephosphorylation of JNK and the expression of MAPK phosphatase-1. Thus, NSC-741909-mediated inhibition of JNK dephosphorylation results in sustained JNK activation, which leads to apoptosis in cancer cells.

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