Inhibiting JNK dephosphorylation and induction of apoptosis by novel anticancer agent NSC-741909 in cancer cells.
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.
From the Departments of Thoracic and Cardiovascular Surgery, Houston, Texas 77030.
Xiaoli
X
Wei
From the Departments of Thoracic and Cardiovascular Surgery, Houston, Texas 77030.
Wei
W
Guo
From the Departments of Thoracic and Cardiovascular Surgery, Houston, Texas 77030.
Shuhong
S
Wu
From the Departments of Thoracic and Cardiovascular Surgery, Houston, Texas 77030.
Li
L
Wang
Systems Biology, Houston, Texas 77030.
Yiling
Y
Lu
Protein Biosynthesis and Biomarker Core Laboratory, University of Texas Medical Branch, Galveston, Texas 77555.
Bo
B
Xu
Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Jinsong
J
Liu
From the Departments of Thoracic and Cardiovascular Surgery, Houston, Texas 77030. Electronic address: bfang@mdanderson.org.
Bingliang
B
Fang
D000873:Anthracenes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation
D000873:Anthracenes; D000970:Antineoplastic Agents; D017931:DNA Primers; D007211:Indoles; C544349:NSC-741909; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases