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BMP4-Smad signaling pathway mediates adriamycin-induced premature senescence in lung cancer cells.

ABSTRACT: Cell senescence, an irreversible cell cycle arrest, reflects a safeguard program that limits the capacity of uncontrolled cell proliferation. Treatment of tumor cells with certain chemotherapeutic agents activates premature senescence to decrease the tumorigenecity. Here we show that sublethal concentrations of adriamycin could induce premature senescence in lung cancer cells. Adriamycin treatment resulted in the up-regulation of BMP4, which is underexpressed in NSCLC (non-small cell lung cancers). Moreover, the BMP4-Smad pathway played a key role in mediating adriamycin-induced senescence. Overexpression of BMP4 was able to induce premature senescence in lung cancer cells and this process required the participation of cyclin/cyclin-dependent kinase (cdk) inhibitors p16(INK4a) and p21(WAF1/cip1). We also show that increases of p16(INK4a) and p21(WAF1/cip1) expression in response to BMP4 were mediated by the Smad signaling pathway. Furthermore, our data revealed that p300 was recruited to P16(INK4a) and P21(WAF1/cip1) promoters by Smad1/5/8 to induce the hyperacetylation of histones H3 and H4 at the promoters. The present study provides useful clues to the evaluation of the potentiality of BMP4 as a responsive molecular target for cancer chemotherapy.

SUBMITTER: Su D

PROVIDER: S-EPMC2673284 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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BMP4-Smad signaling pathway mediates adriamycin-induced premature senescence in lung cancer cells.

Su Dongmei D Zhu Shan S Han Xuefang X Feng Yunpeng Y Huang Hui H Ren Guoling G Pan Lina L Zhang Yu Y Lu Jun J Huang Baiqu B

The Journal of biological chemistry 20090306 18

Cell senescence, an irreversible cell cycle arrest, reflects a safeguard program that limits the capacity of uncontrolled cell proliferation. Treatment of tumor cells with certain chemotherapeutic agents activates premature senescence to decrease the tumorigenecity. Here we show that sublethal concentrations of adriamycin could induce premature senescence in lung cancer cells. Adriamycin treatment resulted in the up-regulation of BMP4, which is underexpressed in NSCLC (non-small cell lung cancer ...[more]

PMID: 19269967

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Project description:AimTo investigate epigenomic and gene expression alterations during cellular senescence induced by oncogenic Raf.MethodsCellular senescence was induced into mouse embryonic fibroblasts (MEFs) by infecting retrovirus to express oncogenic Raf (RafV600E). RNA was collected from RafV600E cells as well as MEFs without infection and MEFs with mock infection, and a genome-wide gene expression analysis was performed using microarray. The epigenomic status for active H3K4me3 and repressive H3K27me3 histone marks was analyzed by chromatin immunoprecipitation-sequencing for RafV600E cells on day 7 and for MEFs without infection. These data for Raf-induced senescence were compared with data for Ras-induced senescence that were obtained in our previous study. Gene knockdown and overexpression were done by retrovirus infection.ResultsAlthough the expression of some genes including secreted factors was specifically altered in either Ras- or Raf-induced senescence, many genes showed similar alteration pattern in Raf- and Ras-induced senescence. A total of 841 commonly upregulated 841 genes and 573 commonly downregulated genes showed a significant enrichment of genes related to signal and secreted proteins, suggesting the importance of alterations in secreted factors. Bmp2, a secreted protein to activate Bmp2-Smad signaling, was highly upregulated with gain of H3K4me3 and loss of H3K27me3 during Raf-induced senescence, as previously detected in Ras-induced senescence, and the knockdown of Bmp2 by shRNA lead to escape from Raf-induced senescence. Bmp2-Smad inhibitor Smad6 was strongly repressed with H3K4me3 loss in Raf-induced senescence, as detected in Ras-induced senescence, and senescence was also bypassed by Smad6 induction in Raf-activated cells. Different from Ras-induced senescence, however, gain of H3K27me3 did not occur in the Smad6 promoter region during Raf-induced senescence. When comparing genome-wide alteration between Ras- and Raf-induced senescence, genes showing loss of H3K27me3 during senescence significantly overlapped; genes showing H3K4me3 gain, or those showing H3K4me3 loss, also well-overlapped between Ras- and Raf-induced senescence. However, genes with gain of H3K27me3 overlapped significantly rarely, compared with those with H3K27me3 loss, with H3K4me3 gain, or with H3K4me3 loss.ConclusionAlthough epigenetic alterations are partly different, Bmp2 upregulation and Smad6 repression occur and contribute to Raf-induced senescence, as detected in Ras-induced senescence.

Dataset Information

BMP4-Smad signaling pathway mediates adriamycin-induced premature senescence in lung cancer cells.

Publications

BMP4-Smad signaling pathway mediates adriamycin-induced premature senescence in lung cancer cells.

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