AP-1 blockade in breast cancer cells causes cell cycle arrest by suppressing G1 cyclin expression and reducing cyclin-dependent kinase activity

Liu, Yongmin; Lü, Chunhua; Shen, Qiang; Muñoz-Medellin, Debbie; Kim, Heetae; Brown, Powel H.

doi:10.1038/sj.onc.1207889

Cited by 63 publications

(58 citation statements)

References 36 publications

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“…Increased AP-1 activity promotes apoptosis in certain cell types, while promoting survival in others. The ectopic expression of c-Jun or c-Fos can induce apoptosis in mouse fibroblasts, sympathetic neurons and human colorectal carcinoma cell lines (38,39). In this study, apicidin induced the activation of c-Jun but had no effect on the levels of c-Fos protein in both cell lines.…”

Section: Discussionmentioning

confidence: 65%

Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

Park

Im²,

Kim³

et al. 2008

Int J Mol Med

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Abstract. The cellular susceptibility of cancer cells to histone deacetylase (HDAC) inhibitors is increased by the etopic expression of oncogenic Ras. However, the ability of HDAC inhibitors to regulate the apoptotic pathway in human breast cancer cells is still not completely understood. In this study, the anti-proliferative effects of apicidin were compared in Hras-transformed human breast epithelial (MCF10A-ras) and non-transformed epithelial (MCF10A) cells. MCF10A-ras cells showed a significantly higher growth rate than MCF10A cells. Apicidin significantly increased the levels of acetylated histone H3 and H4 in both cell lines. Western blot analysis and flow cytometry were used to determine if the anti-proliferative effects of apicidin in MCF10A and MCF10A-ras cells could be mediated by modulating the cell cycle. Apicidin attenuated the expression of cyclin E and CDK2 in MCF10A cells, decreased cyclin D1 and cyclin E levels in MCF10A-ras cells, and increased the levels of CDK inhibitors, p21WAF1/Cip1 and p27Kip1 , in both cell lines. Notably, the levels of hyperphosphorylation of the Rb protein levels were lower in the MCF10A-ras cells after apicidin treatment. Studies on the regulation of apoptosis showed that apicidin induces the upregulation of p53 and the downstream activation of ERK in MCF10A-ras cells. The up-regulation of p53 promoted Bax expression leading to activation of caspases-9 and -6, and eventually to apoptosis in MCF10A-ras cells. In addition, apicidin significantly increased the levels of ERK1/2 phosphorylation in MCF10A-ras cells. Therefore, the apicidinmediated ERK pathway appears to play an important role in modulating the pro-apoptotic pathway in MCF10A-ras cells.

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Section: Discussionmentioning

confidence: 65%

Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

Park

Im²,

Kim³

et al. 2008

Int J Mol Med

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“…In a human fibrosarcoma cell line, TAM67 inhibits AP-1 activity and arrests cells predominately in the G1 phase of the cell cycle (Hennigan and Stambrook, 2001). AP-1 blockade in breast cancer cells induces G1 cell-cycle block, which is associated with decreases in G1 cyclin expression and cyclin-dependent kinase activity (Liu et al, 2004). Moreover, TAM67 inhibits entrance into the S phase after serum stimulation in colon cancer cells (Suto et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…These findings suggest rather restrictive roles of cJun in the acquisition of anchorage independence in the process of human lung carcinogenesis. In breast and colon cancer cells, however, inhibition of cJun has been shown to induce G1 cell arrest on anchorage-dependent conditions (Liu et al, 2004;Suto et al, 2004). In addition, its effects on in vivo tumour growth of lung cancer cells have not been investigated.…”

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confidence: 99%

Growth inhibition of non-small cell lung cancer cells by AP-1 blockade using a cJun dominant-negative mutant

et al. 2008

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cJun, a major constituent of AP-1 transcription factor transducing multiple mitogen growth signals, is frequently overexpressed in nonsmall cell lung cancers (NSCLCs). The purpose of this study is to determine the effects of AP-1 blockade on the growth of NSCLC cells using a cJun dominant-negative mutant, TAM67. Transiently transfected TAM67 inhibited AP-1 transcriptional activity in NSCLC cell lines, NCI-H1299 (H1299), A549 and NCI-H520 (H520). The colony-forming efficiency of H1299 and A549 was reduced by TAM67, while that of H520 was not. To elucidate the effects of TAM67 on the growth of H1299, we established H1299 clone cells that expressed TAM67 under the control of a doxycycline-inducible promoter. In the H1299 clone cells, the induced TAM67 inhibited anchorage-dependent growth by promoting G1 cell-cycle block, but not by apoptosis. The induced TAM67 decreased the expression of a cell-cycle regulatory protein, cyclin A. TAM67 also inhibited anchorage-independent growth of these cells. Furthermore, TAM67 reduced growth of established xenograft tumours from these cells in nude mice. These results suggest that AP-1 plays an essential role in the growth of at least some of NSCLC cells.

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“…Deregulated expression of c-Jun induces immortalised rat fibroblasts to grow in an anchorage-independent fashion (Schütte et al, 1989) depending on the induction of multiple c-Jun target genes Leaner et al, 2003Leaner et al, , 2005Hommura et al, 2004;Katabami et al, 2005). Recent studies reported that specific AP-1 blockade by a dominantnegative mutant of c-Jun, TAM67, inhibited the growth of some types of human cancer cells by causing G1 arrest (Ludes-Meyers et al, 2001;Liu et al, 2004;Suto et al, 2004).…”

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confidence: 99%

Simultaneous blockade of AP-1 and phosphatidylinositol 3-kinase pathway in non-small cell lung cancer cells

et al. 2008

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c-Jun is a major constituent of AP-1 transcription factor that transduces multiple mitogen growth signals, and it is frequently overexpressed in non-small cell lung cancers (NSCLCs). Earlier, we showed that blocking AP-1 by the overexpression of a c-Jun dominant-negative mutant, TAM67, inhibited NSCLC cell growth. The phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathway is important in transformation, proliferation, survival and metastasis of NSCLC cells. In this study, we used NCI-H1299 Tet-on clone cells that express TAM67 under the control of inducible promoter to determine the effects of inhibition of AP-1 and PI3K on cell growth. The PI3K inhibitor, LY294002, produced a dose-dependent inhibition of growth in H1299 cells and that inhibition was enhanced by TAM67. TAM67 increased dephosphorylation of Akt induced by LY294002 and reduced the TPA response element DNA-binding of phosphorylated c-Jun. TAM67 increased G1 cell cycle blockade induced by LY294002, which was partially associated with cyclin A decrease and p27 Kip1 accumulation. Furthermore, TAM67 and LY294002 act, at least additively, to inhibit anchorage-independent growth of the H1299 cells. These results suggest that AP-1 and PI3K/Akt pathways play an essential role in the growth of some NSCLC cells.

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AP-1 blockade in breast cancer cells causes cell cycle arrest by suppressing G1 cyclin expression and reducing cyclin-dependent kinase activity

Cited by 63 publications

References 36 publications

Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

Growth inhibition of non-small cell lung cancer cells by AP-1 blockade using a cJun dominant-negative mutant

Simultaneous blockade of AP-1 and phosphatidylinositol 3-kinase pathway in non-small cell lung cancer cells

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