Extracellular signal-regulated kinase induces cyclin D1 and Cdk-2 expression and phosphorylation of retinoblastoma in hepatocellular carcinoma

Huynh, Hung; Mai, P. T.; Nguyen, Thi Hong Van; Tan, Puay Hoon; Quach, Thu; Van, Thi Nhu Ngoc; Soo, Khee Chee; Tran, Elizabeth

doi:10.3892/ijo.25.6.1839

Cited by 18 publications

(22 citation statements)

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“…Notably, hyperphosphorylation of the cellcycle regulator retinoblastoma protein (RB) and increased production of cyclin A and E have been implicated in HCC initiation and progression [22,23]. As seen in Fig.…”

Section: Concentration-dependent Effect Of Oleate On Hepg2 Steatosis mentioning

confidence: 90%

Oleate-mediated activation of phospholipase D and mammalian target of rapamycin (mTOR) regulates proliferation and rapamycin sensitivity of hepatocarcinoma cells

2011

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Aims/hypothesis A high-fat diet and obesity are associated with increased risk of liver cancer. Because increased delivery of NEFA to the liver occurs in these conditions, we investigated the involvement of the unsaturated fatty acid oleate in hepatocarcinoma cell proliferation using humanderived hepatocarcinoma cell lines as model systems. Methods Western blotting, FACS analysis and [ 3 H]thymidine incorporation were used to study the signalling pathways and the proliferation of cells cultured for up to 72 h with or without a concentration of oleate considered to be relevant to human pathophysiology (50 μmol/l) or a concentration considered elevated (1 mmol/l). Results In HepG2 cells, proliferation was increased in the presence of 50 μmol/l oleate, but was decreased at 1 mmol/ l. This differential effect was correlated with the activation of the mammalian target of rapamycin complex 1 (mTORC1) and with increased translation of cell cycle regulators. Oleate-mediated mTORC1 activation required phospholipase D activation, which produces phosphatidic acid and is known to render mTORC1 rapamycin resistant.Remarkably, rapamycin resistance was found to affect specifically the mTORC1/eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) branch of the mTORC1 pathway in the presence of 50 μmol/l oleate. Furthermore, inhibition of phosphatidic acid production abolished oleateinduced increases in mTORC1 activity and cyclin A production. Importantly, the same differential effects of oleate on mTORC1 activation, cell cycle regulators and rapamycin resistance were found in SK-Hep1 cells. Conclusions/interpretation Oleate stimulates mTORC1 activation and rapamycin resistance. We propose that rapamycin-derived mTOR inhibitors are likely to be of limited therapeutic use to restrain hepatic tumour growth, particularly in the context of associated obesity.

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Section: Concentration-dependent Effect Of Oleate On Hepg2 Steatosis mentioning

confidence: 90%

Oleate-mediated activation of phospholipase D and mammalian target of rapamycin (mTOR) regulates proliferation and rapamycin sensitivity of hepatocarcinoma cells

2011

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“…The level of cyclin D1, which is involved in cell proliferation and is activated by both the RAF/MEK/ERK and phosphatidylinositol 3-kinase pathways in tumor cells (15,16), was measured after 5 and 16 hours of sorafenib treatment to further characterize the effects of sorafenib on cell proliferation. At a concentration of 10 Amol/L, sorafenib reduced cyclin D1 protein level in both PLC/PRF/5 and HepG2 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Sorafenib Blocks the RAF/MEK/ERK Pathway, Inhibits Tumor Angiogenesis, and Induces Tumor Cell Apoptosis in Hepatocellular Carcinoma Model PLC/PRF/5

et al. 2006

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Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinomas (HCC). Sorafenib (BAY 43-9006, Nexavar) is a multikinase inhibitor with activity against Raf kinase and several receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. In this study, we investigated the in vitro effects of sorafenib on PLC/PRF/5 and HepG2 HCC cells and the in vivo antitumor efficacy and mechanism of action on PLC/ PRF/5 human tumor xenografts in severe combined immunodeficient mice. Sorafenib inhibited the phosphorylation of MEK and ERK and down-regulated cyclin D1 levels in these two cell lines. Sorafenib also reduced the phosphorylation level of eIF4E and down-regulated the antiapoptotic protein Mcl-1 in a MEK/ ERK-independent manner. Consistent with the effects on both MEK/ERK-dependent and MEK/ERK-independent signaling pathways, sorafenib inhibited proliferation and induced apoptosis in both HCC cell lines. In the PLC/PRF/5 xenograft model, sorafenib tosylate dosed at 10 mg/kg inhibited tumor growth by 49%. At 30 mg/kg, sorafenib tosylate produced complete tumor growth inhibition. A dose of 100 mg/kg produced partial tumor regressions in 50% of the mice. In mechanism of action studies, sorafenib inhibited the phosphorylation of both ERK and eIF4E, reduced the microvessel area (assessed by CD34 immunohistochemistry), and induced tumor cell apoptosis (assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling) in PLC/PRF/5 tumor xenografts. These results suggest that the antitumor activity of sorafenib in HCC models may be attributed to inhibition of tumor angiogenesis (VEGFR and PDGFR) and direct effects on tumor cell proliferation/survival (Raf kinase signalingdependent and signaling-independent mechanisms).

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“…Although the initial signaling cascade through which cyclin D1 is activated remains unidentified, the MEK/ERK1/2 pathway could be a possible candidate. Cyclin D1 can be transcriptionally activated through Ras/ERK pathway (22), and it has been reported that in HepG2 the ectopic expression of activated MEK1, a member of the Ras/ERK pathway, induces overexpression of cyclin D1 and Cdk2, which results in increased proportion of cells in S phase without changing the fraction of cells in G1 (21). These data are consistent with our results, since after 12 h of stimulation overexpression of cyclin D1 was detected, accompanied with increased proportion of cells in S phase, Figure 6.…”

Section: Discussionmentioning

confidence: 99%

“…The present work investigates the expression and activation, during and after CRet treatment, of three key proteins in cell cycle regulation: cyclin D1, which regulates the G1 phase and its transition to S, and is synthesized in response to exogenous factors (18)(19)(20)(21)(22), cyclin A, which controls the S and G2 phases (23,24) and cyclin B1, involved in the regulation of the initiation and control of early mitotic stages (25). Since these cyclins become activated by binding to cyclin-dependent kinases or CDKs, the present study also analyzes the expression and activation of p27 Kip1 , a cyclin-dependent kinase inhibitor (CKI).…”

Section: Introductionmentioning

confidence: 99%

Cytostatic response of HepG2 to 0.57 MHz electric currents mediated by changes in cell cycle control proteins

Hernández-Bule

Cid²,

Trillo³

et al. 2010

Int J Oncol

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Abstract. The capacitive-resistive electric transfer (CRet) therapy is a non-invasive technique that applies electrical currents of 0.4-0.6 MHz to the treatment of musculoskeletal injuries. Although this therapy has proved effective in clinical studies, its interaction mechanisms at the cellular level still are insufficiently investigated. Results from previous studies have shown that the application of CRet currents at subthermal doses causes alterations in cell cycle progression and decreased proliferation in hepatocarcinoma (HepG2) and neuroblastoma (NB69) human cell lines. The aim of the present study was to investigate the antiproliferative response of HepG2 to CRet currents. The results showed that 24-h intermittent treatment with 50 μA/mm 2 current density induced in HepG2 statistically significant changes in expression and activation of cell cycle control proteins p27Kip1 and cyclins D1, A and B1. The chronology of these changes is coherent with that of the alterations reported in the cell cycle of HepG2 when exposed to the same electric treatment. We propose that the antiproliferative effect exerted by the electric stimulus would be primarily mediated by changes in the expression and activation of proteins intervening in cell cycle regulation, which are among the targets of emerging chemical therapies. The capability to arrest the cell cycle through electrically-induced changes in cell cycle control proteins might open new possibilities in the field of oncology.

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Extracellular signal-regulated kinase induces cyclin D1 and Cdk-2 expression and phosphorylation of retinoblastoma in hepatocellular carcinoma

Cited by 18 publications

References 0 publications

Oleate-mediated activation of phospholipase D and mammalian target of rapamycin (mTOR) regulates proliferation and rapamycin sensitivity of hepatocarcinoma cells

Oleate-mediated activation of phospholipase D and mammalian target of rapamycin (mTOR) regulates proliferation and rapamycin sensitivity of hepatocarcinoma cells

Sorafenib Blocks the RAF/MEK/ERK Pathway, Inhibits Tumor Angiogenesis, and Induces Tumor Cell Apoptosis in Hepatocellular Carcinoma Model PLC/PRF/5

Cytostatic response of HepG2 to 0.57 MHz electric currents mediated by changes in cell cycle control proteins

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