Inhibiting JNK Dephosphorylation and Induction of Apoptosis by Novel Anticancer Agent NSC-741909 in Cancer Cells
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.
- SourceAvailable from: Shuhong Wu
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- "NSC-741909 is an analogue of oncrasin-1 which we identified as an anticancer agent through cell-based synthetic lethality screening (Guo et al. 2008). Testing of NCI-60 cell lines showed that NSC-741909 has a unique anticancer spectrum and is effective against a number of cancer cell lines derived from lung, colon, ovarian, kidney and breast cancers, suggesting its novel mechanisms (Wei et al.2009). Molecular characterization of NSC-741909 revealed that NSC-741909-induced activation of MAPK (including p38, JNK, and ERK) in sensitive cells and that suppression of MAPK dephosphorylation could be the primary cause of MAPK activation. "
ABSTRACT: NSC-741909 (1-[(4-chlorophenyl)methyl]-1H-Indole-3-methanol) is a novel anticancer agent that is highly active against several NCI-60 cancer cell lines. This agent induces sustained activation of mitogen-activated protein kinases (MAPK), including JNK and p38 MAP kinases. However, the mechanisms of its selective antitumor activity in some cancer cell lines remain unknown. We tested the combined effects of NSC-741909 and several kinase inhibitors that target the Raf/MEK/ERK1/2 or PI3K/AKT pathways in two sensitive lung cancer cells. We found that PD98059 (2'-amino-3'-methoxyflavone), a flavone derivative and a selective MEK inhibitor, can dramatically block the cell killing effect of NSC-741909. To determine whether this inhibitory effect is associated with MEK inhibition or other mechanisms, we evaluated the effects of other MEK inhibitors with different chemical structures and flavone derivatives that do not have an effect on MEK. We found that several flavonoids can markedly block NSC-741909-induced apoptosis and JNK activation in a time-dependent manner, regardless of whether they inhibit MEK or not. In contrast, NSC-741909-induced JNK activation and apoptosis were not blocked by other MEK-specific inhibitors U0126 and CI1040. Our results also showed that NSC-741909 induced a dramatic increase of reactive oxygen species in sensitive cells and that flavonoids effectively blocked the NSC-741909-induced reactive oxygen species production which are associated with flavonoids' antagonistic effects on NSC-741909-induced JNK activation and apoptosis. Those results demonstrated that flavonoids-mediated antagonist effect is through scavenging of reactive oxygen species. Our results may have implication on the design of clinical evaluation of antitumor activity of NSC-741909 or its analogues.European journal of pharmacology 12/2010; 649(1-3):51-8. DOI:10.1016/j.ejphar.2010.08.057 · 2.68 Impact Factor
- European Journal of Integrative Medicine 12/2009; 1(4):219-220. DOI:10.1016/j.eujim.2009.08.142 · 0.65 Impact Factor
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ABSTRACT: Recent advances in high throughput, high content "omic" technologies coupled with clinical information has lead to the expectation that the complexity of the molecular information generated will lead to more robust scientific research as well as the expectation that overarching therapeutic approaches will be patient-tailored to the underlying specific molecular defects of the disease. As disease understanding progresses and more therapeutics, which predominately target proteins, are developed there is a need to more confidently determine the protein signaling events that can be correlated with drug response since the deranged protein signaling networks are often the drug target itself. In this environment, the Reverse Phase Protein Microarray (RPMA) can be utilized to address the needs of both clinical screening and disease understanding through its ability to provide an unmatched functional and highly multiplexed signaling network level mapping of ongoing signaling activation, coupled with the ability of the platform to provide this information reproducibly from a tiny needle biopsy specimen or fine needle aspirate. This platform has now been utilized for biomarker discovery/validation and advancements in disease understanding both in the clinic and at the bench in the fields of cancer, liver disease, immunological disorders, and bacterial infection.Disease markers 06/2010; 28(4):225-32. DOI:10.3233/DMA-2010-0705 · 2.17 Impact Factor