Inhibition of eukaryotic elongation factor-2 confers to tumor suppression by a herbal formulation Huanglian-Jiedu decoction in human hepatocellular carcinoma

Wang, Ning; Feng, Yibin; Tan, Hor‐Yue; Cheung, Fanny M.; Hong, Ming; Lao, Lixing; Nagamatsu, Tadashi

doi:10.1016/j.jep.2015.02.025

Cited by 44 publications

(34 citation statements)

References 41 publications

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“…Besides eEF2 and eEF2 kinase were found to be possible drug targets in gastrointestinal and breast cancer [19, 31]. Wang et al reported a tumor suppressing activity of the herbal formulation Huanglian Jiedu Decoction by activating the eEF2 kinase and thus inhibiting eEF2 in HCC [32]. Contrary, Tekedereli and colleagues reported that a siRNA-silencing of eEF2 kinase resulted in growth inhibition of tumor cells [31].…”

Section: Discussionmentioning

confidence: 99%

Eukaryotic elongation factor 2 is a prognostic marker and its kinase a potential therapeutic target in HCC

et al. 2017

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Hepatocellular carcinoma is a cancer with increasing incidence and largely refractory to current anticancer drugs. Since Sorafenib, a multikinase inhibitor has shown modest efficacy in advanced hepatocellular carcinoma additional treatments are highly needed. Protein phosphorylation via kinases is an important post-translational modification to regulate cell homeostasis including proliferation and apoptosis. Therefore kinases are valuable targets in cancer therapy. To this end we performed 2D differential gel electrophoresis and mass spectrometry analysis of phosphoprotein-enriched lysates of tumor and corresponding non-tumorous liver samples to detect differentially abundant phosphoproteins to screen for novel kinases as potential drug targets. We identified 34 differentially abundant proteins in phosphoprotein enriched lysates. Expression and distribution of the candidate protein eEF2 and its phosphorylated isoform was validated immunohistochemically on 78 hepatocellular carcinoma and non-tumorous tissue samples. Validation showed that total eEF2 and phosphorylated eEF2 at threonine 56 are prognostic markers for overall survival of HCC-patients. The activity of the regulating eEF2 kinase, compared between tumor and non-tumorous tissue lysates by in vitro kinase assays, is more than four times higher in tumor tissues. Functional analyzes regarding eEF2 kinase were performed in JHH5 cells with CRISPR/Cas9 mediated eEF2 kinase knock out. Proliferation and growth is decreased in eEF2 kinase knock out cells.ConclusioneEF2 and phosphorylated eEF2 are prognostic markers for survival of hepatocellular carcinoma patients and the regulating eEF2 kinase is a potential drug target for tumor therapy.

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Section: Discussionmentioning

confidence: 99%

Eukaryotic elongation factor 2 is a prognostic marker and its kinase a potential therapeutic target in HCC

et al. 2017

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“…Wang et al [49] found that HLJDD (Huanglian Jiedu decoction), a traditional Chinese medicine that has been shown to have anti-cancer growth and anti-metastasis effects in clinical practice, can inhibit the proliferation of HepG2 hepatoma cells but is less potent in inhibiting the proliferation of MHCC97L cells (another type of hepatocellular carcinoma). This agent can also suppress angiogenesis (assessed using CD31 as an endothelial cell marker) and the growth of hepatocellular carcinoma xenografts (MHCC97L cells into nude mice).…”

Section: Wwwnaturecom/aps Liu R Et Almentioning

confidence: 99%

Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases

Proud

2016

Acta Pharmacol Sin

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Eukaryotic elongation factor 2 kinase (eEF2K) is an unusual protein kinase that regulates the elongation stage of protein synthesis by phosphorylating and inhibiting its only known substrate, eEF2. Elongation is a highly energy-consuming process, and eEF2K activity is tightly regulated by several signaling pathways. Regulating translation elongation can modulate the cellular energy demand and may also control the expression of specific proteins. Growing evidence links eEF2K to a range of human diseases, including cardiovascular conditions (atherosclerosis, via macrophage survival) and pulmonary arterial hypertension, as well as solid tumors, where eEF2K appears to play contrasting roles depending on tumor type and stage. eEF2K is also involved in neurological disorders and may be a valuable target in treating depression and certain neurodegenerative diseases. Because eEF2K is not required for mammalian development or cell viability, inhibiting its function may not elicit serious side effects, while the fact that it is an atypical kinase and quite distinct from the vast majority of other mammalian kinases suggests the possibility to develop it into compounds that inhibit eEF2K without affecting other important protein kinases. Further research is needed to explore these possibilities and there is an urgent need to identify and characterize potent and specific small-molecule inhibitors of eEF2K. In this article we review the recent evidence concerning the role of eEF2K in human diseases as well as the progress in developing small-molecule inhibitors of this enzyme.

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“…It has been used to treat cancer particularly liver cancer. It inhibits HCC cell proliferation at its nontoxic doses and suppresses growth and angiogenesis in a xenograft mouse model (Wang et al ., ). This regimen is composed of four herbal species: Coptis chinensis Franch.…”

Section: Herbal Medicine Used For Clinical Hcc Treatmentmentioning

confidence: 97%

“…A recent study has found that HLJDD can suppress the synthesis of nascent protein by inactivating eukaryotic elongation factor‐2 (eEF2) without deregulating the translation initiation factors and the major components in HLJDD, geniposide, berberine, and baicalin. HLJDD can also reduce the phosphorylation of eukaryotic elongation factor‐2 kinase, the negative regulator of eEF2, by suppressing the AMPK/mTOR signaling pathway in HCC (Wang et al ., ). Moreover, HLJDT significantly increases the expression of inactivated phospho‐Cdc2 and phospho‐Cdc25C, and decreases the levels of cyclin A, cyclin B1, Cdc2, and Cdc25C.…”

Section: Herbal Medicine Used For Clinical Hcc Treatmentmentioning

confidence: 97%

Herbal Medicine Offered as an Initiative Therapeutic Option for the Management of Hepatocellular Carcinoma

Chen

Qiu

et al. 2016

Phytother. Res.

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Hepatocellular carcinoma (HCC) is a common malignant cancer and is the third leading cause of death worldwide. Effective treatment of this disease is limited by the complicated molecular mechanism underlying HCC pathogenesis. Thus, therapeutic options for HCC management are urgently needed. Targeting the Wnt/β-catenin, Hedgehog, Notch, and Hippo-YAP signaling pathways in cancer stem cell development has been extensively investigated as an alternative treatment. Herbal medicine has emerged as an initiative therapeutic option for HCC management because of its multi-level, multi-target, and coordinated intervention effects. In this article, we summarized the recent progress and clinical benefits of targeting the above mentioned signaling pathways and using natural products such as herbal medicine formulas to treat HCC. Proving the clinical success of herbal medicine is expected to deepen the knowledge on herbal medicine efficiency and hasten the adoption of new therapies. Copyright © 2016 John Wiley & Sons, Ltd.

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Inhibition of eukaryotic elongation factor-2 confers to tumor suppression by a herbal formulation Huanglian-Jiedu decoction in human hepatocellular carcinoma

Abstract: Our results indicate that HLJDD has potential in blocking HCC progression with involvement of eEF2 inhibition.

Cited by 44 publications

References 41 publications

Eukaryotic elongation factor 2 is a prognostic marker and its kinase a potential therapeutic target in HCC

Eukaryotic elongation factor 2 is a prognostic marker and its kinase a potential therapeutic target in HCC

Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases

Herbal Medicine Offered as an Initiative Therapeutic Option for the Management of Hepatocellular Carcinoma

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