Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes

Vick, Binje; Weber, Achim; Urbanik, Toni; Maass, T; Teufel, Andreas; Krammer, Peter H.; Opferman, Joseph T.; Schuchmann, Marcus; Galle, Peter R.; Schulze‐Bergkamen, Henning

doi:10.1002/hep.22664

Cited by 137 publications

(154 citation statements)

References 75 publications

(62 reference statements)

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“…Results from our study and other investigators support Mcl-1 as a key mediator of cell survival and drug resistance in hepatocellular carcinoma (5,6,27,28). Mcl-1 may be suppressed by sorafenib through downregulation of E2F1, which also suppress cyclin E1 expression in hepatocellular carcinoma cells.…”

Section: Discussionsupporting

confidence: 80%

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

Hsu

Lin

Cheng

et al. 2016

Clinical Cancer Research

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Purpose: To clarify the effects of cyclin E1 suppression on antitumor efficacy of sorafenib in hepatocellular carcinoma cells and to explore the potential of combining sorafenib with cyclindependent kinase (CDK) inhibition in therapy.Experimental Design: The effects of cyclin E1 suppression on sorafenib-induced apoptosis were tested in both sorafenibsensitive (Huh-7 and HepG2, IC 50 5-6 mmol/L) and sorafenib-resistant (Huh-7R and HepG2R, IC 50 14-15 mmol/L) hepatocellular carcinoma cells. The activity of pertinent signaling pathways and the expression of cell cycle and apoptosisrelated proteins were measured using Western blotting. Efficacy of sorafenib combined with the pan-CDK inhibitor flavopiridol was tested both in vitro and in xenograft experiments. The pertinent downstream mediators of antitumor efficacy were tested in transient transfection and RNA interference experiments.Results: Cyclin E1 mRNA and protein expressions were suppressed after sorafenib treatment in sorafenib-sensitive but not in sorafenib-resistant hepatocellular carcinoma cells. Changes in cyclin E2 or D1 were not correlated with sorafenib sensitivity. The knockdown of cyclin E1 expression reversed the resistance of hepatocellular carcinoma cells to sorafenib in terms of cell growth and apoptosis induction, whereas the overexpression of cyclin E1 increased the resistance to sorafenib. The growth-inhibitory and apoptosis-inducing effects of sorafenib were enhanced by flavopiridol, and Mcl-1 suppression was determined to play a critical role in mediating this enhancing effect.Conclusions: The cyclin E1 suppression in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib efficacy. The combination of sorafenib and CDK inhibitors may improve the efficacy of sorafenib in hepatocellular carcinoma.

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Section: Discussionsupporting

confidence: 80%

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

Hsu

Lin

Cheng

et al. 2016

Clinical Cancer Research

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“…Given the importance of the viral regulatory protein HBx in the pathogenesis of HBV-related liver diseases (1,24,42) and the importance of the antiapoptotic molecule Mcl-1 in liver homeostasis (18,59), the aims of this work were to evaluate whether susceptibility of hepatocytes to In this study, the dose of cisplatin we used did not trigger apparent cell death in control hepatocytes, consistent with some previous observations (35,36), while it did induce significant apoptosis in HBx-expressing hepatocytes. In addition, both nude mice bearing HBx-expressing tumor xenografts and HBx-Tg mice were more sensitive than control mice to cisplatin injury.…”

Section: Discussionsupporting

confidence: 75%

“…Mcl-1 belongs to the antiapoptotic members of the Bcl-2 family, localizes primarily at the outer mitochondrial membrane, and is an important regulator of mitochondrion-mediated apopto-sis by sequestering proapoptotic BH3-only molecules such as Bim, Bid, and Puma and preventing the oligomerization and activation of multidomain proapoptotic members Bax and Bak (25,63). Recent work has demonstrated that hepatocyte-specific deletion of Mcl-1 increases spontaneous hepatocyte apoptosis, resulting in chronic liver damage and fibrogenesis (18,59), triggers compensatory hepatocellular proliferation, and causes HCC (62), highlighting a crucial role for this prosurvival protein in liver homeostasis. Despite this, however, it remains unexplored whether Mcl-1 is involved in hepatic injury due to HBV reactivation induced by chemotherapy.…”

mentioning

confidence: 99%

Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1

Chen

Liang

et al. 2011

J Virol

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“…Mcl1 is best known as a potent survival factor for hematopoietic, hepatocytic and dermal precursor cells (Opferman et al, 2005;Opferman et al, 2003;Sitailo et al, 2009;Vick et al, 2009). In the nervous system, Mcl1 is also required for the survival of embryonic and adult NPCs (Arbour et al, 2008;Malone et al, 2012).…”

Section: Deletion Of Either P57mentioning

confidence: 99%

Mcl1 regulates the terminal mitosis of neural precursor cells in the mammalian brain through p27Kip1

et al. 2013

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SUMMARYCortical development requires the precise timing of neural precursor cell (NPC) terminal mitosis. Although cell cycle proteins regulate terminal mitosis, the factors that influence the cell cycle machinery are incompletely understood. Here we show in mice that myeloid cell leukemia 1 (Mcl1), an anti-apoptotic Bcl-2 protein required for the survival of NPCs, also regulates their terminal differentiation through the cell cycle regulator p27 Kip1 . A BrdU-Ki67 cell profiling assay revealed that in utero electroporation of Mcl1 into NPCs in the embryonic neocortex increased NPC cell cycle exit (the leaving fraction

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Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes

Cited by 137 publications

References 75 publications

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

Hepatitis B Virus X Protein Enhances Cisplatin-Induced Hepatotoxicity via a Mechanism Involving Degradation of Mcl-1

Mcl1 regulates the terminal mitosis of neural precursor cells in the mammalian brain through p27Kip1

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