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

Shuhong Wu,Bingliang Fang,Jinsong Liu,Wei Guo,Yiling Lu,Li Wang,Xiaoli Wei,Bo Xu

doi:10.1074/jbc.m109.010256

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.

Highlights

Because a compound targeting to such a partner can be identified by their lethality when administered to cancer cells with elevated activities of a particular oncogene
Molecular characterization revealed that oncrasin-1 can induce abnormal aggregation of protein kinase C-␫ in the nucleus of oncrasin-sensitive cells but not in oncrasin-resistant cells and that oncrasin-1-induced apoptosis was blocked by siRNA3 of K-Ras or protein kinase C-␫ [3], demonstrating that oncrasin-1 is synthetically lethal for K-Ras and protein kinase C-␫, one of the downstream effectors of Ras signaling pathways [4]
Our results indicated that sustained c-Jun N-terminal protein kinase (JNK) activation caused by suppression of JNK dephosphorylation contributes to NSC-741909-induced apoptosis

Summary

Introduction

Because a compound targeting to such a partner can be identified by their lethality when administered to cancer cells with elevated activities of a particular oncogene. NSC-741909mediated inhibition of JNK dephosphorylation results in sustained JNK activation, which leads to apoptosis in cancer cells.

Results

Conclusion