Bortezomib effect on E2F and cyclin family members in human hepatocellular carcinoma cell lines

Daniele, Bruno; Dapas, Barbara; Farra, Rossella; Scaggiante, Bruna; Pozzato, Gabriele; Zanconati, Fabrizio; Fiotti, Nicola; Consoloni, Lara; Chiaretti, Sara; Grassi, Gabriele

doi:10.3748/wjg.v20.i3.795

Cited by 34 publications

(28 citation statements)

References 31 publications

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Section: Chemotherapy-induced Responsessupporting

confidence: 62%

“…Similar differences in E2F8 expression levels were also reported in a recent study where the effects of the proteasome inhibitor bortezomib (BZB) on atypical E2Fs was evaluated in hepatocellular 29 carcinoma cells (Baiz, Dapas et al 2014). BZB treatment of the hepatocyte-like hepatocellular carcinoma cells had a significant impact on E2F8 by reducing its levels (Baiz, Dapas et al 2014). Interestingly, BZB treatment had an effect only on E2F8 levels but E2F7 mRNA levels remained unchanged (Baiz, Dapas et al 2014), suggesting a chemotherapeutic agent-dependent mechanism of action.…”

Section: Chemotherapy-induced Responsessupporting

confidence: 61%

“…BZB treatment of the hepatocyte-like hepatocellular carcinoma cells had a significant impact on E2F8 by reducing its levels (Baiz, Dapas et al 2014). Interestingly, BZB treatment had an effect only on E2F8 levels but E2F7 mRNA levels remained unchanged (Baiz, Dapas et al 2014), suggesting a chemotherapeutic agent-dependent mechanism of action.…”

Section: Chemotherapy-induced Responsesmentioning

confidence: 86%

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The role of E2F7 and E2F8 in squamous differentiation, UV- and chemotherapy-induced responses in keratinocytes

Rethinam¹

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Among keratinocyte-derived squamous cell carcinoma (SCC), cutaneous SCC (CSCC) is the second most common cutaneous cancer type and the most common of the potentially fatal skin cancers. Approximately 90% of head and neck cancers are SCC (HNSCC) and HNSCC worldwide is the sixth most common cancer type afflicting mankind. While resectable disease may be treated by surgery with radiation or chemoradiation, there are still no curative options for advanced, unresectable disease. However, chemotherapy alone may offer a hope for unresectable, disseminated SCC, where 50-60% of patients have disease recurrence within 2 years and approximately 30% of these develop metastatic disease. The mainstay of chemotherapeutic treatment in SCC is the platinum-based drug, cisplatin, 5-fluorouracil (5-FU), taxanes, and anti-EGFR monoclonal antibody such as Cetuximab. Nonetheless, despite advances in treatment techniques, the 5-year survival rate still remains at around 55%.Therefore, there remains a lack of options for recurrent or metastatic disease.The E2F family of transcription factors has emerged as key regulators of proliferation, differentiation and response to stress and apoptotic stimuli in keratinocytes. Consistent with these roles, dysregulation of E2F expression/activity is a common occurrence in cancer and SCC in particular. Thus, better understanding of the E2F family of proteins is essential to establish how these processes are disrupted during SCC genesis. The E2F network exists as a complex map of interacting pathways, and the complete understanding of the E2F family will not be possible until physiological functions of newly identified inhibitory E2F proteins, E2F7 and E2F8, are fully revealed. I provide strong evidence, from in vitro experiments, that E2F7 plays a unique and non-redundant role in modulating UV-or chemotherapy-induced cytotoxicity whereas E2F8 has a unique and non-redundant capacity to regulate squamous differentiation. In addition, I report on a unique feedback loop between E2F1, E2F7 and E2F8 that highlights a previously unreported interdependent axis.With respect to E2F7-specific functions, my work characterised two previously unidentified pathways as therapeutic targets, E2F7/Sphk1/S1P/AKT and E2F7/RacGAP1/AKT, by which the transcription factor E2F7 suppresses doxorubicin specific sensitivity in SCC cells.Targeting these pathways has the potential to expand the clinical activity of existing chemotherapeutics. I provide, in vitro, in vivo and patient data in this study that shows that E2F7-dependent repression of doxorubicin sensitivity is mediated via the induction of Sphingosine kinase 1 (Sphk1) and Rac GTPase activating protein 1 (RacGAP1). These are iii both novel findings and have significant implications for drug resistant SCC. Specifically, Ishowed that (i) E2F7 is overexpressed in patient SCCs and inhibits sensitivity to doxorubicin, (ii) that E2F7-dependent doxorubicin resistance is mediated via E2F-dependent induction of Sphk1 leading to overproduction of Sphingosine-1-phosphate ...

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Section: Chemotherapy-induced Responsessupporting

confidence: 62%

Section: Chemotherapy-induced Responsessupporting

confidence: 61%

Section: Chemotherapy-induced Responsesmentioning

confidence: 86%

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The role of E2F7 and E2F8 in squamous differentiation, UV- and chemotherapy-induced responses in keratinocytes

Rethinam¹

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“…It can promote cell apoptosis [80,81] by reducing p-Akt levels [82][83][84] and inducing autophagy via proteasome independent mechanisms [85]. BZB was also shown to suppress HCC cell proliferation by increasing the levels of cell cycle inhibitors p27/p21 [79,86,87], and reducing the levels of cyclin D1 [87,88], the phosphorylated form of pRB, and the transcription factor E2F1 [87][88][89][90].…”

Section: Bortezomibmentioning

confidence: 96%

The ubiquitin–proteasome system and its potential application in hepatocellular carcinoma therapy

Chen

Shen

2016

Cancer Letters

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“…16HBE human bronchial epithelial cells or JHH6 hepatocellular carcinoma cells (Baiz et al, 2014) were grown in Dulbecco's modified Eagle's medium (DMEM) and William's medium, respectively, with 10% fetal bovine serum (FBS) and 1% of penicillin/streptomycin (100 U/ml penicillin and 100 mg/ml streptomycin), at 37°C in 5% CO 2 humidified atmosphere. DMEM and the other cell culture constituents were purchased from Euroclone.…”

Section: Cell Culturementioning

confidence: 99%

Development of a simple, biocompatible and cost-effective Inulin-Diethylenetriamine based siRNA delivery system

Sardo

Farra

Licciardi

et al. 2015

European Journal of Pharmaceutical Sciences

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Bortezomib effect on E2F and cyclin family members in human hepatocellular carcinoma cell lines

Abstract: The differential expression of E2Fs and related genes induced by BZB in diverse HCC cell phenotypes contribute to bortezomib's mechanism of action in hepatocellular carcinoma.

Cited by 34 publications

References 31 publications

The role of E2F7 and E2F8 in squamous differentiation, UV- and chemotherapy-induced responses in keratinocytes

The role of E2F7 and E2F8 in squamous differentiation, UV- and chemotherapy-induced responses in keratinocytes

The ubiquitin–proteasome system and its potential application in hepatocellular carcinoma therapy

Development of a simple, biocompatible and cost-effective Inulin-Diethylenetriamine based siRNA delivery system

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