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J Cancer Res Clin Oncol. 2010 Mar;136(3):437-45. doi: 10.1007/s00432-009-0674-5. Epub 2009 Sep 2.

P53 and p38 MAPK pathways are involved in MONCPT-induced cell cycle G2/M arrest in human non-small cell lung cancer A549.

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1
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, #388 Yuhangtang Road, Hangzhou, Zhejiang, 310058, China.

Abstract

PURPOSE:

In previous research, we found that 10-methoxy-9-nitrocamptothecin (MONCPT) possessed potent anti-tumor activity in A549 cells in vitro and in vivo. In this paper, our purpose is to investigate the mechanism of MONCPT-induced cell cycle arrest in A549 cells.

METHODS:

Cell cycle distribution was measured using flow cytometry (FCM). Protein expression and RNA expression were analyzed by western blotting and real-time PCR, respectively. SiRNA technology was introduced to silence the expression of p53 and p38.

RESULTS:

FCM showed that MONCPT induced cell cycle G2/M arrest in time- and dose-dependent manner. The levels of feedback loop proteins PLK-1, Cdc25C, and cyclinB1 were obviously increased from 12 to 24 h, and then reduced from 36 to 48 h by MONCPT (100.0 nM). Moreover, down-regulation of p-AKT in A549 cells was seen after treated with 100.0 nM MONCPT for 12-48 h. Over-expression of p53 and p21 in A549 cells treated with MONCPT was observed in time-dependent manner. When wild type p53 expression was specifically inhibited by RNA-interference, A549 cells treated with MONCPT delayed the onset of G2/M arrest; meanwhile p-ERK and Cdc2 were up-regulated while p21 and CDK7 were down-regulated in A549 cells treated with MONCPT and p53 SiRNA transfection in contrast to cells treated with 100.0 nM MONCPT alone. In addition, our results exhibited that MONCPT obviously down-regulated p-ERK, JNK, p-JNK, and p-p38. Treatment with p38 mitogen-activated protein kinase (MAPK) SiRNA obviously inhibited p38 MAPK and delayed the G2/M arrest induced by 50.0 nM MONCPT after 48 h.

CONCLUSION:

Cell cycle regulators, AKT, p53, and MAPK, as therapeutic targets for MONCPT to induce cell cycle G2/M arrest in the context of anticancer therapy.

PMID:
19727814
DOI:
10.1007/s00432-009-0674-5
[Indexed for MEDLINE]
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