Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis

Leers, Mathie P.G.; Kölgen, Wendy; Björklund, Viveka; Bergman, Tomas; Tribbick, Gordon; Persson, Bengt; Björklund, Peter; Ramaekers, Frans C. S.; Björklund, Bertil; Nap, Marius; Jörnvall, Hans; Schütte, B.

doi:10.1002/(sici)1096-9896(199904)187:5<567::aid-path288>3.0.co;2-j

Cited by 587 publications

(395 citation statements)

References 13 publications

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“…Compared with well-differentiated NET, both a high mitotic count and a high apoptotic ratio, as highlighted by the 70% positive m30 expression, characterized this subgroup of tumors. 63,64 In addition, for the first time to our knowledge, we demonstrated the increased expression of VEGF and Ku in LCNEC, which may represent potential future therapeutic targets. To our knowledge, only p16 expression and, more recently, c-kit expression have emerged as potential but not confirmed biologic markers that may have prognostic significance.…”

Section: Discussionmentioning

confidence: 64%

Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas

Faggiano

Sabourin

Ducreux

et al. 2007

Cancer

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BACKGROUND.Poorly differentiated large cell neuroendocrine carcinomas (LCNEC) comprise a rare and still scarcely known subgroup of neuroendocrine tumors. The objective of this study was to investigate the epidemiology, clinical presentation, prognostic factors, and molecular pathways of patients with poorly differentiated LCNEC.METHODS.Forty‐one patients who had a confirmed diagnosis of poorly differentiated LCNEC according to the criteria of the most recent World Health Organization classification of neuroendocrine tumors of the lung entered the study. The clinicopathologic features of patients with poorly differentiated LCNEC were reviewed, prognostic parameters for their survival were studied, and the prognostic roles of the proteins involved in cell cycle regulation were investigated with tissue array analysis in a subset of patients with LCNEC.RESULTS.Twenty‐four men and 17 women with a median age of 63 years (age range, 26–81 years) who had LCNEC were studied. LCNEC developed after therapy for a first cancer in 14% of patients. Neither a personal or familial history of endocrine tumors nor a primary association that was compatible with an inherited syndrome was observed. The increase of at least 1 serum biologic marker was observed in 93% of patients. A primary tumor was identified in only 63% patients. Thirty‐one patients had distant metastases, and 10 patients had only lymph node metastases at the time of the diagnosis. The 5‐year survival rate was 24%. High mitotic count, low expression of neuroendocrine markers, and a Bcl‐2/Bax ratio > 1 were unfavorable prognostic factors for survival (P < .01). All patients who had isolated peripheral lymph node LCNEC achieved a cure.CONCLUSIONS.The results from this study highlighted distinctive clinical features and prognostic indicators of poorly differentiated LCNEC. Peripheral isolated lymph node clinical presentation is proposed as a new clinical entity. Cancer 2007. © 2007 American Cancer Society.

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Section: Discussionmentioning

confidence: 64%

Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas

Faggiano

Sabourin

Ducreux

et al. 2007

Cancer

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“…Even the formation of a C-terminal epitope by cleavage of cytokeratin (KRT)18 at Asp-397 (Leers et al, 1999), considered highly diagnostic for caspase activity, was not prevented. Also, cleavage of the classical caspase substrate poly (ADP-ribose) polymerase (PARP) to its p85 fragment was present in this condition ( Figure 4a) (Nicholson et al, 1995).…”

Section: Treatment With Taxol Results In Detachment and Apoptosis Of mentioning

confidence: 99%

Mechanistic insight into taxol-induced cell death

et al. 2008

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We analysed the involvement of proteases during taxolmediated cell death of human A549 non-small-cell lung carcinoma cells using a proteomics approach that specifically targets protein N termini and further detects newly formed N termini that are the result of protein processing. Our analysis revealed 27 protease-mediated cleavages, which we divided in sites C-terminal to aspartic acid (Asp) and sites C-terminal to non-Asp residues, as the result of caspase and non-caspase protease activities, respectively. Remarkably, some of the former were insensitive to potent pancaspase inhibitors, and we therefore suggest that previous inhibitor-based studies that report on the caspaseindependent nature of taxol-induced cell death should be judged with care. Furthermore, many of the sites C-terminal to non-Asp residues were also uniquely observed in a model of cytotoxic granule-mediated cell death and/or found by in vitro cataloging human l-calpain substrates using a similar proteomics technique. This thus raises the hypothesis that killing tumor cells by chemotherapy or by immune cells holds similar non-Asp-specific proteolytic components with strong indications to calpain activity.

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“…29 The act-casp-3 antibody detects a cleavage product of one of the key executioners of apoptosis, activatedcaspase-3. 30 M30 and act-casp-3 antibodies were used to detect the relevant markers of apoptosis within monolayer transduced PHKs using immunocytochemistry (Fig.…”

Section: Lmb Induces Apoptosis In Monolayer Phks Expressing Hpv Oncogmentioning

confidence: 99%

Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes

Gray¹,

Bjelogrlić²,

Appleyard³

et al. 2007

Intl Journal of Cancer

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Human papillomavirus (HPV) infection is strongly associated with the development of anogenital neoplasia, particularly cervical cancer. It has been estimated that 99.7% of all cervical carcinomas are attributable to infection with HPV, and types 16 and 18 account for the vast majority of such cases. Both of these Ôhigh riskÕ HPV types encode the oncoproteins E6 and E7, which exert multiple effects on many proteins involved in cell-cycle regulation, including p53. The nuclear export protein inhibitor leptomycin B (LMB) has been shown to cause the nuclear sequestration of p53 in cervical carcinoma cells. We demonstrate that LMB induces apoptosis selectively at nanomolar concentrations in primary human keratinocytes (PHKs) expressing HPV oncogenes. Both monolayer and organotypic raft cultures of transduced PHKs were highly susceptible to treatment with LMB. By contrast, although LMB stimulated p53 accumulation in normal PHKs, no significant induction of apoptosis was detected on Western blots or immunostained monolayer/raft cells, or following pulsed exposure to the drug. Furthermore, topical application of lM concentrations of LMB to mouse skin was non-toxic. These data suggest that the topical application of LMB to HPV-infected intra-epithelial lesions may represent a specific and effective therapeutic strategy against HPV-associated anogenital neoplasia. ' 2007 Wiley-Liss, Inc.Key words: human papillomavirus; leptomycin B; keratinocytes; oncogenes; apoptosis Leptomycin B (LMB), a secondary metabolite produced by Streptomyces spp., 1 inhibits the export of proteins containing a nuclear export signal (NES) from the nucleus to the cytoplasm. This is achieved through inactivation of the nuclear export receptor protein CRM1 (exportin 1) by covalent modification. 2,3 LMB therefore promotes nuclear accumulation of NES proteins, including the tumour suppressor protein p53. 4,5 Furthermore, LMB has been shown to cause nuclear sequestration and reactivation of p53 in cervical carcinoma cell lines containing human papillomavirus (HPV) and this was associated with induction of apoptosis. 6,7 By contrast, LMB treatment resulted in the reversible cell-cycle arrest of both rat fibroblasts 8 and normal human primary fibroblasts. 5,9 Although the effect of LMB on CRM1 is well documented, the specific molecular mechanism(s) by which LMB induces cellcycle arrest and apoptosis still remain unclear.Since the discovery of LMB in the early 1980s, there has been considerable interest in the use of the compound as a cancer therapeutic. LMB (alternatively termed CI-940, elactocin or PD 114, 720) and its hydroxy analogue (PD 114, 721) were shown to possess potent activity against 7 different tumour models. 10 Based on these encouraging findings, a phase I clinical trial was initiated to assess the systemic administration of LMB. However, the trial was later terminated because of unwanted side effects. 11 Nevertheless, although there are difficulties in using LMB systemically, topical therapeutic use may be feasible.Cervical cancer is the ...

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Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis

Cited by 587 publications

References 13 publications

Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas

Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas

Mechanistic insight into taxol-induced cell death

Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes

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