Depletion of Raf-1 protooncogene by geldanamycin causes apoptosis in human luteinized granulosa cells

Khan, Shah M.; Oliver, Rush H.; Dauffenbach, Lisa M.; Yeh, John

doi:10.1016/s0015-0282(00)00633-6

Cited by 14 publications

(10 citation statements)

References 32 publications

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“…Raf-1 plays an important role in the regulation of proliferation, differentiation, and apoptosis (44), and is an attractive target for therapy. Raf-1 inhibition by antisense nucleotide treatment induced potent antiproliferative effects in tumor cell lines (45), and depletion of Raf-1 by treatment with ansamycins induces growth inhibition and apoptosis of tumor cells (46,47). We confirmed the down-regulation of c-Raf-1 with EC5 treatment and antitumor activity in HNSCC.…”

Section: Discussionsupporting

confidence: 65%

Potent Activity of a Novel Dimeric Heat Shock Protein 90 Inhibitor against Head and Neck Squamous Cell Carcinoma In vitro and In vivo

Yin

Zhang

Burrows

et al. 2005

Clinical Cancer Research

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Heat shock protein 90 (Hsp90) is a molecular chaperone that promotes the conformational maturation of numerous client proteins, many of which play critical roles in tumor cell growth and survival. The ansamycin-based Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in phase I/II clinical testing. However, 17-AAG is difficult to formulate and displays weak activity against some tumors. A novel dimeric ansamycin, EC5, was evaluated for antitumor activity in eight head and neck squamous cell carcinoma (HNSCC) cell lines. Both 17-AAG and EC5 inhibited tumor cell proliferation effectively, but EC5 was more potent, with IC 50 below 200 nmol/L in most cell lines tested, including several lines that were resistant to 17-AAG. The inability of 17-AAG to kill JHU12 cells was linked to a defect in retinoblastoma signaling and could be rescued by ectopic expression of p16 INK4a. EC5 induced G 1 growth arrest of tumor cells and apoptosis, with the degradation of client proteins including epidermal growth factor receptor, c-Raf-1, Akt, and Cdk4 and inhibition of Akt phosphorylation. In vivo, EC5 dramatically reduced the growth rate of established HNSCC xenografts in nude mice and decreased expression of epidermal growth factor receptor and Akt within the xenografts.These results suggest that this novel ansamycin-based Hsp90 inhibitor affects multiple pathways involved in tumor development and progression and may represent a new strategy for the treatment of HNSCC patients.

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Section: Discussionsupporting

confidence: 65%

Potent Activity of a Novel Dimeric Heat Shock Protein 90 Inhibitor against Head and Neck Squamous Cell Carcinoma In vitro and In vivo

Yin

Zhang

Burrows

et al. 2005

Clinical Cancer Research

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“…Subsequently, Raf-1 inhibition by antisense nucleotide treatment induced potent antiproliferative effects in tumor cell lines. In addition, depletion of Raf-1 by treatment with ansamycins induced growth inhibition and apoptosis of tumor cells (37,38). This process could be of particular importance in TT genotypes, in which Gas expression is increased.…”

Section: Discussionmentioning

confidence: 97%

Overall and Relapse-Free Survival in Oropharyngeal and Hypopharyngeal Squamous Cell Carcinoma Are Associated with Genotypes of T393C Polymorphism of the GNAS1 Gene

Lehnerdt¹,

Franz²,

Zaqoul³

et al. 2008

Clinical Cancer Research

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Purpose: In previous studies, we have shown that theTallele of a specific single-nucleotide polymorphism (SNP) in the Gas gene (T393C) correlates with increased Gas expression and hence apoptosis. The T allele was associated with a favorable outcome in a variety of human cancers, e.g., carcinoma of the urinary bladder, kidney, and colorectum. Experimental Design: The prognostic value of theT393C SNP was evaluated in an unselected series of patients treated with curative intent for oropharyngeal and hypopharyngeal squamous cell carcinomas, including all tumor stages with different therapeutic regimens. Genotype analysis was done using DNA from paraffin-embedded tissue samples from 202 patients (162 men, 40 women) with a median follow-up of 38 months (1-133 months). The various genotypes were correlated with relapse-free and overall survival. Results: GNAS1 393C homozygous patients displayed a higher risk for disease progression than T393 homozygous patients (hazard ratio CC versus TT, 1.9; 95% confidence interval, 1.1-3.2; P = 0.019). The same genotype effect was observed for overall survival with CC genotypes at higher risk for death compared with TT genotypes (hazard ratio, 1.7; 95% confidence interval, 1.1-2.9; P = 0.015). Multivariate analysis showed that, besides American Joint Committee on Cancer stage, tumor localization, and gender, the T393C polymorphism was an independent prognostic factor for disease progression and death. Conclusion: The T393C SNP could be considered as a genetic marker to predict the clinical course of patients suffering from oropharyngeal and hypopharyngeal cancer.Head and neck cancer comprises f6% to 7% of all human malignancies (1). Among head and neck cancer, squamous cell carcinoma (SCC) is the most common histologic subgroup, overall (80-85% of oropharyngeal and 97% of hypopharyngeal carcinomas; ref.2) representing the sixth most frequent cancer worldwide (3). Annually, about 400,000 head and neck SCC (HNSCC) are diagnosed worldwide, most of which are locally advanced at presentation. Some tumor sites, like the hypopharynx (4), imply a particularly bad prognosis among HNSCC due to the lack of obvious symptoms in the early disease stage. Surgery and/or radiochemotherapy are the mainstay of locoregional treatment in these patients (5). For previously untreated advanced stage resectable cancers in the oral cavity, oropharynx, and hypopharynx, the standard therapy regimens of surgery and postoperative radiation therapy result in a 5-year survival rate of only 40% to 50% (6). Because of an already extensive locoregional involvement upon admission, one third of patients with HNSCC have nonresectable tumors (7). Nonresectable advanced tumors are currently treated by combined radiochemotherapy with a 5-year overall survival rate of almost 30% (8). Chemotherapy alone has a modest favorable effect upon outcome; patients with recurrent or metastatic disease receiving chemotherapy show a median survival ranging from 6 to 9 months (9). Poor distant disease control rates in this par...

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“…Since geldanamycin is known to induce apoptosis and some but not all cell types (40,49,53) and, as mentioned above, caspase activity seems involved in ErbB-2 degradation induced by this drug, we tested other known inducers of apoptosis for their capacity to provoke ErbB-2 degradation and formation of the 23-kDa fragment. Of the various inducers of apoptosis tested, two compounds (staurosporin and curcumin) were found to promote formation of a 23-kDa fragment.…”

Section: Discussionmentioning

confidence: 99%

“…ErbB-2 Degradation by Staurosporin-Geldanamycin induces ErbB-2 degradation, in part through a caspase-dependent mechanism, and geldanamycin is known to induce apoptosis in some cell lines (40). Therefore, we tested whether other reported inducers of apoptosis, particularly in mammary carcinoma cell lines, also provoke ErbB-2 degradation.…”

Section: Erbb-2 Degradationmentioning

confidence: 99%

Caspase-dependent Cleavage of ErbB-2 by Geldanamycin and Staurosporin

Tikhomirov

Carpenter

2001

Journal of Biological Chemistry

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The geldanamycin-induced degradation of ErbB-2 produces a 23-kDa carboxyl-terminal fragment, which has been isolated and subjected to amino-terminal microsequencing. The obtained sequence indicates that the amino terminus of this fragment corresponds to Gly-1126 of ErbB-2. Analysis of the residues immediately before Gly-1126 suggests that cleavage may involve caspase activity. Site-directed mutagenesis of Asp-1125 in ErbB-2 prevents geldanamycin-provoked formation of the 23-kDa fragment, consistent with the requirement of this residue for caspase-dependent cleavage in known substrates. Also, the addition of the pan-caspase inhibitor Z-VAD-FMK blocks formation of the 23-kDa ErbB-2 fragment in cells exposed to geldanamycin. Interestingly, staurosporin and curcumin are also shown to provoke the degradation of ErbB-2 with formation of the 23-kDa carboxyl-terminal fragment. The generation of this fragment by staurosporin or curcumin is likewise blocked by caspase inhibition. Caspase inhibition does not prevent accelerated degradation of the 185-kDa native ErbB-2 in geldanamycin-treated cells but does significantly prevent staurosporin-stimulated metabolic loss of ErbB-2.ErbB-2, a Type I transmembrane receptor tyrosine kinase, functions as a co-receptor by dimerizing with ligand-occupied members of the ErbB family, the EGF receptor, ErbB-3, or ErbB-4 (1-3). This heterodimerization event is considered to alter the signaling capacity and cellular responses provoked by homodimers of occupied ErbB receptors. No ligand has been identified that directly interacts with the ectodomain of ErbB-2.ErbB-2 was originally identified as the transforming oncogene neu, which contains a point mutation in the transmembrane domain that is responsible for its oncogenic potential (4). Overexpression of ErbB-2 also produces a transformed phenotype in experimental systems (5-7). Importantly, ErbB-2 is frequently overexpressed in carcinomas, particularly mammary and ovarian carcinomas, and is associated with a poor prognosis (8 -10). ErbB-2 antibodies (11, 12) and agents such as interferon (13) or tyrosine kinase inhibitors (14) decrease the growth of ErbB-2-expressing tumor cells and also reduce the cellular level of ErbB-2 (15). In many of these instances the decreased growth provoked by the loss of ErbB-2 is due to increased apoptosis. In contrast, the overexpression of ErbB-2 can prevent the induction of apoptosis (15). Hence, the growth-controlling activity of ErbB-2 is related to structural changes or alterations in its level of expression.The benzoquinoid anasamycin antibiotic geldanamycin was first isolated and described as an inhibitor of tyrosine kinase activity (16). Subsequently, geldanamycin was shown to possess tumoricidal activity toward cell lines that overexpress ErbB-2 (17). Currently geldanamycin derivatives designed to reduce toxicity are in clinical trials for certain cancer patients (18). The addition of geldanamycin to cells results in an increased rate of degradation of several protein kinases, including ErbB-2 (17), S...

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Depletion of Raf-1 protooncogene by geldanamycin causes apoptosis in human luteinized granulosa cells

Cited by 14 publications

References 32 publications

Potent Activity of a Novel Dimeric Heat Shock Protein 90 Inhibitor against Head and Neck Squamous Cell Carcinoma In vitro and In vivo

Potent Activity of a Novel Dimeric Heat Shock Protein 90 Inhibitor against Head and Neck Squamous Cell Carcinoma In vitro and In vivo

Overall and Relapse-Free Survival in Oropharyngeal and Hypopharyngeal Squamous Cell Carcinoma Are Associated with Genotypes of T393C Polymorphism of the GNAS1 Gene

Caspase-dependent Cleavage of ErbB-2 by Geldanamycin and Staurosporin

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