Bortezomib arrests the proliferation of hepatocellular carcinoma cells HepG2 and JHH6 by differentially affecting E2F1, p21 and p27 levels

Daniele, Bruno; Pozzato, Gabriele; Dapas, Barbara; Farra, Rossella; Scaggiante, Bruna; Grassi, Mario; Uxa, Laura; Giansante, Carlo; Zennaro, Cristina; Guarnieri, Gianfranco; Grassi, Gabriele

doi:10.1016/j.biochi.2008.10.015

Cited by 62 publications

(57 citation statements)

References 16 publications

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“…The strong elevation of p21 transcripts seems to be a general phenomenon because it was observed in 3 ERa-positive breast cancer cell lines. To our knowledge, only one study from Baiz and colleagues indicated a transcriptional regulation of p21 by bortezomib in hepatocellular cells (44). Moreover, we provide evidence indicating that silencing of ERa prevents the bortezomib effects on both p21 expression and cell growth inhibition.…”

Section: Discussionsupporting

confidence: 56%

Roles of Estrogen Receptor and p21Waf1 in Bortezomib-Induced Growth Inhibition in Human Breast Cancer Cells

Maynadier¹,

Shi²,

Vaillant³

et al. 2012

Molecular Cancer Research

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Section: Discussionsupporting

confidence: 56%

Roles of Estrogen Receptor and p21Waf1 in Bortezomib-Induced Growth Inhibition in Human Breast Cancer Cells

Maynadier¹,

Shi²,

Vaillant³

et al. 2012

Molecular Cancer Research

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“…An inhibitory effect of TGF-β on proteasomal degradation of the cyclin-dependent kinase inhibitor p27 has also been described [30]. BZ was shown to arrest the proliferation of hepatocellular carcinoma cells by differentially affecting p21 and p27 levels [31]. In addition, BZ treatment also significantly increased p21 mRNA in an ischemia/reperfusion model [32].…”

Section: Discussionmentioning

confidence: 99%

The Proteasome Inhibitor Bortezomib Prevents Lupus Nephritis in the NZB/W F1 Mouse Model by Preservation of Glomerular and Tubulointerstitial Architecture

Hainz

Thomas

Neubert

et al. 2012

Nephron Exp Nephrol

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Background/Aims: Crucial steps in the initiation of lupus nephritis are the deposition of (auto-)antibodies and consequent complement activation. In spite of aggressive treatment patients may develop terminal renal failure. Therefore, new treatment strategies are needed. In extension to our previously published data we here analyzed the potential renoprotective mechanisms of bortezomib (BZ) in experimental lupus nephritis by focusing on morphological changes. Methods: Female NZB×NZW F1 mice develop lupus-like disease with extensive nephritis that finally leads to lethal renal failure. Treatment with 0.75 mg/kg BZ i.v. or placebo (PBS) twice per week started at 18 or 24 weeks of age. Antibody production was measured with ELISA and kidney damage was determined by quantitative morphological and immunohistochemical methods. Results: BZ treatment completely inhibited antibody production in both BZ-treated groups and prevented the development of nephritis in comparison to PBS-treated animals. Glomerular and tubulointerstitial damage scores, collagen IV expression, mean glomerular volume as well as tubulointerstitial proliferation and apoptosis were significantly lower after BZ treatment. Glomerular ultrastructure and in particular podocyte damage and loss were prevented by BZ treatment. Conclusions: BZ effectively prevents the development of nephritis in the NZB/W F1 mouse model. Specific protection of podocyte ultrastructure may critically contribute to renoprotection by BZ, which may also represent a potential new treatment option in human lupus nephritis.

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“…Total RNA extraction; the evaluation of RNA quality, integrity, and quantification; reverse transcription; and polymerase chain reaction amplification were performed as previously described (15), except that the primers for cyclin E2, 2′,5′-oligoadenylate synthetase 1 (OAS1) and 28S ribosomal RNA were forward 5′-CTTCCAAACTTGAGGAAATC-3′/ reverse 5′-TCCATCCTTAAGATATCCTC-3′, forward 5′-TCCAAGGTGGTAAAG GGTGG-3′/reverse 5′-AGGTCAGCGT CAGATCGGC-3′, and forward 5′-TGGGAATGCAGCCCAAAG-3′/reverse 5′-CCTTACGGTACTTGTTGACTATGC-3′, respectively. The annealing temperatures for each primer couple were 56°C, 62°C, and 60°C, respectively.…”

Section: Quantitative Reversetranscription-polymerase Chain Reaction mentioning

confidence: 99%

Role of E2F1-Cyclin E1-Cyclin E2 Circuit in Human Coronary Smooth Muscle Cell Proliferation and Therapeutic Potential of Its Downregulation by siRNAs

Dapas

Farra

Grassi

et al. 2009

Mol Med

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Aberrant coronary vascular smooth muscle cell (CSMC) proliferation is a pivotal event underlying intimal hyperplasia, a phenomenon impairing the long-term efficacy of bypass surgery and angioplasty procedures. Consequently research has become focused on efforts to identify molecules that are able to control CSMC proliferation. We investigated downregulation of CSMC growth by small interfering RNAs (siRNAs) targeted against E2F1, cyclin E1, and cyclin E2 genes, whose contribution to CSMC proliferation is only now being recognized. Chemically synthesized siRNAs were delivered by two different transfection reagents to asynchronous and synchronous growing human CSMCs cultivated either in normo-or hyperglycemic conditions. The depletion of each of the three target genes affected the expression of the other two genes, demonstrating a close regulatory control. The clearest effects associated with the inhibition of the E2F1-cyclin E1/E2 circuit were the reduction in the phosphorylation levels of the retinoblastoma protein pRB and a decrease in the amount of cyclin A2. At the phenotypic level the downmodulation of CSMC proliferation resulted in a decrease of S phase matched by an increase of G1-G0 phase cell amounts. The antiproliferative effect was cell-donor and transfectant independent, reversible, and effective in asynchronous and synchronous growing CSMCs. Importantly, it was also evident in hyperglycemia, a condition that underlies diabetes. No significant aspecific cytotoxicity was observed. Our data demonstrate the interrelation among E2F1-cyclin E1-cyclin E2 and the pivotal role this circuit exerts in CSMC proliferation. Additionally, our work validates the concept of utilizing anti-E2F1-cyclin E1-cyclin E2 siRNAs to develop a potential novel therapy to control intimal hyperplasia.

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Bortezomib arrests the proliferation of hepatocellular carcinoma cells HepG2 and JHH6 by differentially affecting E2F1, p21 and p27 levels

Cited by 62 publications

References 16 publications

Roles of Estrogen Receptor and p21Waf1 in Bortezomib-Induced Growth Inhibition in Human Breast Cancer Cells

Roles of Estrogen Receptor and p21Waf1 in Bortezomib-Induced Growth Inhibition in Human Breast Cancer Cells

The Proteasome Inhibitor Bortezomib Prevents Lupus Nephritis in the NZB/W F1 Mouse Model by Preservation of Glomerular and Tubulointerstitial Architecture

Role of E2F1-Cyclin E1-Cyclin E2 Circuit in Human Coronary Smooth Muscle Cell Proliferation and Therapeutic Potential of Its Downregulation by siRNAs

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