The Natural Anticancer Compounds Rocaglamides Inhibit the Raf-MEK-ERK Pathway by Targeting Prohibitin 1 and 2

Polier, Gernot; Neumann, Jennifer; Thuaud, Frédéric; Ribeiro, Nigel; Gelhaus, Christoph; Schmidt, Hannelore; Giaisi, Marco; Köhler, Rebecca; Müller, Wolfgang W.; Proksch, Peter; Leippe, Matthias; Janßen, Ottmar; Désaubry, Laurent; Krammer, Peter H.; Li‐Weber, Min

doi:10.1016/j.chembiol.2012.07.012

Cited by 141 publications

(179 citation statements)

References 52 publications

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“…Consistent with the former observations, 12 the protein levels of CDK4, cyclin D3, Cdc25A and Cdc25B were down-regulated after Roc-A treatment in a time-dependant manner (Fig. 1g).…”

Section: Roc-a Suppresses Expression Of Key Proteins Involved In G1-ssupporting

confidence: 90%

“…To measure the time resolved gene responses to Roc-A, RNA was isolated from Roc-A-treated (50 nM) normal T and Jurkat T cells at t 5 [0, 1,2,3,4,6,8,10,14,20,28,36] and t 5 [0. 5,1,2,3,4,5,6,7,8,10,12,14,16,20,24,28,32,36] hr, respectively. The quality of total RNA was controlled with an Agilent 2100 Bioanalyzer (Agilent Technologies GmbH, Berlin, Germany).…”

Section: Rna Preparation and Dna Microarray Analysismentioning

confidence: 99%

“…8,[10][11][12] One can predict that translation inhibition would consequently lead to downregulation of protein expression, particularly of those proteins having a short half-life such as CDK4, cyclin D and Cdc25. 1,[16][17][18][19] However, we noticed that Cdc25A was degraded upon Roc-A treatment with a much faster rate (with a half-life of less than 15 min) than Cdc25B, CDK4, CDK6 and cyclin D3 (Fig.…”

Section: Roc-a Suppresses Expression Of Key Proteins Involved In G1-smentioning

confidence: 99%

“…[9][10][11] Recently, we have identified that prohibitin (PHB) 1 and 2, which are required for activation of the Ras-CRaf-MEK-ERK signaling pathway, are direct targets of Roc. 12 Blocking PHB function by Roc resulted in down-regulation of cyclin D3, CDK4, CDK6 and Cdc25A. 12 In this study, we further investigate the precise mechanisms by which Roc targets the regulatory components of the cell cycle machinery of cancer cells.…”

mentioning

confidence: 98%

“…12 Blocking PHB function by Roc resulted in down-regulation of cyclin D3, CDK4, CDK6 and Cdc25A. 12 In this study, we further investigate the precise mechanisms by which Roc targets the regulatory components of the cell cycle machinery of cancer cells. Using the first identified Roc compound, Rocaglamide-A (Roc-A; 1H-2, 3, 3a, 8b-tetrahydrocyclopenta[b]benzofuran), 13 we identified a new action of Roc.…”

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confidence: 98%

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The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

et al. 2013

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Targeting the cancer cell cycle machinery is an important strategy for cancer treatment. Cdc25A is an essential regulator of cycle progression and checkpoint response. Over-expression of Cdc25A occurs often in human cancers. In this study, we show that Rocaglamide-A (Roc-A), a natural anticancer compound isolated from the medicinal plant Aglaia, induces a rapid phosphorylation of Cdc25A and its subsequent degradation and, thereby, blocks cell cycle progression of tumor cells at the G1-S phase. Roc-A has previously been shown to inhibit tumor proliferation by blocking protein synthesis. In this study, we demonstrate that besides the translation inhibition Roc-A can induce a rapid degradation of Cdc25A by activation of the ATM/ATRChk1/Chk2 checkpoint pathway. However, Roc-A has no influence on cell cycle progression in proliferating normal T lymphocytes. Investigation of the molecular basis of tumor selectivity of Roc-A by a time-resolved microarray analysis of leukemic vs. proliferating normal T lymphocytes revealed that Roc-A activates different sets of genes in tumor cells compared with normal cells. In particular, Roc-A selectively stimulates a set of genes responsive to DNA replication stress in leukemic but not in normal T lymphocytes. These findings further support the development of Rocaglamide for antitumor therapy.In normal cells, the cell division cycle is tightly controlled. Cancer cells are characterized by deregulation in the cell division cycle, which is associated with increased DNA replication and elevated cellular proliferation. 1-3 Therefore, targeting the cancer cell cycle machinery has been considered to be a rational strategy for cancer treatment. 4 Cell division is governed by cyclin dependent kinases (CDKs) that are tightly regulated by cyclins and CDK inhibitors (CDKIs). Tumor-associated cell cycle defects often show alterations in CDK expression or/and activity. 2 Typically, CDK4 and CDK6 that are crucial for G1 checkpoint control are often over-expressed in many malignancies. 2,3 Evidence shows that deregulation of CDK4 and CDK6 activity is associated with a wide variety of tumors. 2 Moreover, elevated expressions of the cell division cycle 25 (Cdc25) phosphatases, in particular, the isoform Cdc25A, which is essential for cell cycle transitions of G1-S and S-G2, has been shown in different cancers and their over-expression often correlates with more aggressive disease and poor prognosis. 1,5 Recently, genetic studies indicate that CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle. Instead, they are only required for the proliferation of specific cell types. 2 Thus, targeting the activities of CDK2, CDK4 and CDK6 may be a promising approach for cancer treatment.Rocaglamides (Roc; 5 Flavaglines), derived from the traditional Chinese medicinal plant Aglaia, are a group of naturally occurring herbal chemicals. A number of Roc compounds have been shown to possess potent inhibitory effects on tumor growth in vitro and in vivo in animal models with IC 50 concentrations at the n...

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“…Consistent with the former observations, 12 the protein levels of CDK4, cyclin D3, Cdc25A and Cdc25B were down-regulated after Roc-A treatment in a time-dependant manner (Fig. 1g).…”

Section: Roc-a Suppresses Expression Of Key Proteins Involved In G1-ssupporting

confidence: 90%

Section: Rna Preparation and Dna Microarray Analysismentioning

confidence: 99%

Section: Roc-a Suppresses Expression Of Key Proteins Involved In G1-smentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 98%

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The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

et al. 2013

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Bioactive Flavaglines: Synthesis and Pharmacology

Basmadjian¹,

Zhao²,

Gramont³

et al. 2014

Bioactive Natural Products

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A Trifluorinated Thiazoline Scaffold Leading to Pro‐apoptotic Agents Targeting Prohibitins

et al. 2014

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A new class of small molecules, with an unprecedented trifluorothiazoline scaffold, were synthesized and their pro‐apoptotic activity was evaluated. With an EC50 in the low micromolar range, these compounds proved to be potent inducers of apoptosis in a broad spectrum of tumor cell lines, regardless of the functional status of p53. Fast structure–activity relationship studies allowed the preparation of the strongest apoptosis‐inducing candidate. Using a high performance affinity purification approach, we identified prohibitins 1 and 2, key proteins involved in the maintenance of cell viability, as the targets for these compounds.

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The Natural Anticancer Compounds Rocaglamides Inhibit the Raf-MEK-ERK Pathway by Targeting Prohibitin 1 and 2

Cited by 141 publications

References 52 publications

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

Bioactive Flavaglines: Synthesis and Pharmacology

A Trifluorinated Thiazoline Scaffold Leading to Pro‐apoptotic Agents Targeting Prohibitins

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