The Role of Cyclin-dependent Kinase Inhibitor p27Kip1 in Anti-HER2 Antibody-induced G1 Cell Cycle Arrest and Tumor Growth Inhibition

Le, Xiao Feng; Claret, François X.; Lammayot, Amy; Tian, Ling; Deshpande, Deepa; LaPushin, Ruth; Tari, Ana M.; Bast, Robert C.

doi:10.1074/jbc.m300848200

Cited by 135 publications

(131 citation statements)

References 35 publications

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“…HER2 signaling was downregulated trastuzumab or siHER2. As we have previously reported, trastuzumab specifically suppressed the tumor growth of breast cancer cells that overexpress HER2 through induction of G1 arrest associated with upregulation of the CDK inhibitor p27 kip1 and downregulation of CDK2 (Le et al, 2003(Le et al, , 2005b. As shown in Figure 2a, trastuzumab treatment for 24 h did not affect the level of HER2 protein in BT474 cells, which overexpress HER2.…”

Section: Resultssupporting

confidence: 65%

“…In other cell systems, delayed activation of the p38 MAP kinase pathway also has a negative impact on cell proliferation by inducing apoptosis (Daly et al, 1999;Takekawa et al, 2002;Bulavin and Fornace, 2004;Naito et al, 2004). Treatment of BT474 and SKBr3 cells with anti-HER2 antibodies for 72 h does not induce significant apoptosis (Le et al, 2003(Le et al, , 2005a. Instead, trastuzumab-induced TSP-1 expression (Figures 3 and 4), which was mediated by the delayed activation of p38 MAP kinase.…”

Section: Discussionmentioning

confidence: 97%

“…Promising clinical results have also been reported using a combination of trastuzumab, docetaxel, and platinum (Crown and Pegram, 2003). We have reported previously that arresting HER2-overexpressing cancer cells in the G1 phase of the cell cycle by induction of the CDK inhibitor p27 kip1 and reduction of CDK2 is one of the major mechanisms by which trastuzumab inhibits growth of cancer cells in vitro (Le et al, 2003(Le et al, , 2005b. Antibody-dependent cellular cytotoxicity is one of major mechanisms by which anti-HER2 antibodies can exert cytotoxic effects in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Preparation of total protein from cell lines and Western blot analysis were performed as described previously (Le et al, 2003). For extraction of whole lysates from tumor samples, tissues were harvested fresh, washed twice in 1 ml of PBS, and cut into small pieces with scissors or a razor.…”

Section: Preparation Of Total Protein and Western Immunoblot Analysismentioning

confidence: 99%

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HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

et al. 2006

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We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin s ) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro-and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.

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Section: Resultssupporting

confidence: 65%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Preparation Of Total Protein and Western Immunoblot Analysismentioning

confidence: 99%

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HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

et al. 2006

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“…Regulation of p27 kip1 expression and/or intracellular localization is one of the principal mechanisms trough which anti-EGFR and anti-ErbB-2 drugs block cell cycle progression in cancer cells [33][34][35][36][37].…”

Section: Discussionmentioning

confidence: 99%

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells

D’Alessio

Luca

Maiello

et al. 2009

Breast Cancer Res Treat

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International audienceTreatment of breast cancer cells with a combination of the EGFR-tyrosine kinase inhibitor (EGFR-TKI) gefitinib and the anti-ErbB-2 monoclonal antibody trastuzumab results in a synergistic antitumor effect. In this study, we addressed the mechanisms involved in this phenomenon. The activation of signaling pathways and the expression of cell cycle regulatory proteins were studied in SK-Br-3 and BT-474 breast cancer cells, following treatment with EGFR and/or ErbB-2 inhibitors. Treatment with the gefitinib/trastuzumab combination produced, as compared with a single agent, a more prolonged blockade of AKT and MAPK activation, a more pronounced accumulation of cells in the G0/G1 phase of the cell cycle, a more significant increase in the levels of p27 and of hypophosphorylated pRb2, and a decrease in the levels of Cyclin D1 and survivin. Similar findings were observed with the EGFR/ErbB-2 inhibitor lapatinib. Gefitinib, trastuzumab, and their combination increased the stability of p27, with the combination showing the highest effects. Blockade of both receptors with gefitinib/trastuzumab or lapatinib induced a significant increase in the levels of p27 mRNA and in the nuclear levels of the p27 transcription factor FKHRL-1. Inhibition of PI3K signaling also produced a significant raise in p27 mRNA. Finally, down-modulation of FKHRL-1 with siRNAs prevented the lapatinib-induced increase of p27 mRNA. The synergism deriving from EGFR and ErbB-2 blockade is mediated by several different alterations in the activation of signaling proteins and in the expression of cell cycle regulatory proteins, including transcriptional and posttranscriptional regulation of p27 expression

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Mitochondrial Toxicity Induced by Chemotherapeutic Drugs

Ferreira

Coelho

Oliveira

et al. 2018

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

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The Role of Cyclin-dependent Kinase Inhibitor p27Kip1 in Anti-HER2 Antibody-induced G1 Cell Cycle Arrest and Tumor Growth Inhibition

Abstract: Cyclin-dependent kinase (CDK) inhibitor p27

Cited by 135 publications

References 35 publications

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells

Mitochondrial Toxicity Induced by Chemotherapeutic Drugs

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