| The novel antimicrotubule agent cryptophycin 52 (LY355703) induces apoptosis via multiple pathways in human prostate cancer cells. | |
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MedLine Citation:
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PMID: 12473608 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We assessed the ability of cryptophycin 52 (LY355703), a novel antimicrotubule, to induce growth arrest and apoptosis in prostate cancer cell lines and investigated potential molecular mechanisms of death. LNCaP (androgen-dependent) and DU-145 (androgen-independent) cells accumulated in G(2)-M phase of the cell cycle and progressively acquired sub-G(0)-G(1) DNA content after 48 h of exposure to cryptophycin 52 (1-10 pM). Induction of apoptosis was confirmed by DNA ladder formation and detection of cytoplasmic nucleosomes. PC-3 (androgen-independent) cells were less responsive to cryptophycin 52-induced death. Apoptosis was associated with proteolytic processing and activation of the caspase-3-like subfamily proteins caspase-3 and caspase-7 and cleavage of the caspase substrate poly(ADP-ribose) polymerase. The pan-caspase inhibitor BOC-Asp(OMe)-fluoromethylketone effectively reduced cryptophycin 52-induced caspase-3-like protease activity and apoptosis in DU-145 cells. In contrast, BOC-Asp(OMe)-fluoromethylketone did not inhibit apoptosis induction in LNCaP cells by cryptophycin 52, even though both cryptophycin 52-induced caspase-3-like activity and staurosporine-induced death were blocked under identical conditions. Cryptophycin 52 induced phosphorylation of c-raf1 and bcl-2 and/or bcl-x(L) to comparable levels in all cell lines studied, and LNCaP cells overexpressing bcl-2 were more resistant to cryptophycin 52-induced apoptosis. Up-regulation of p53, bax, and p21 expression was induced in wild-type p53-expressing LNCaP cells only after cryptophycin 52 exposure. A sustained increase in c-Jun NH(2)-terminal kinase phosphorylation was also observed, the levels of which strongly correlated with apoptosis. We conclude that apoptosis induced by cryptophycin 52 in prostate cancer cells is androgen status independent, cell type specific for caspase requirement, modulated by the bcl-2 family, linked to but not dependent on p53, and strongly correlated with c-Jun NH(2)-terminal kinase phosphorylation. Cryptophycin 52-induced apoptosis in prostate cancer cells is therefore associated with multiple cell line-specific alterations in apoptosis-associated proteins and pathways. |
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Authors:
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Lisa Drew; Robert L Fine; Tamara N Do; Geoffrey P Douglas; Daniel P Petrylak |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: 8 ISSN: 1078-0432 ISO Abbreviation: Clin. Cancer Res. Publication Date: 2002 Dec |
Date Detail:
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Created Date: 2002-12-10 Completed Date: 2003-01-21 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 3922-32 Citation Subset: IM |
Affiliation:
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Department of Medicine, Division of Medical Oncology, Columbia University, New York, New York 10032, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Androgens
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pharmacology Antineoplastic Agents / pharmacology* Apoptosis / drug effects* Blotting, Western Caspases / metabolism Cell Division / drug effects Cytochrome c Group / metabolism Depsipeptides* Enzyme Activation Enzyme Inhibitors / pharmacology Humans JNK Mitogen-Activated Protein Kinases Lactams / pharmacology* Lactones / pharmacology* Male Microtubules / drug effects* Mitogen-Activated Protein Kinases / metabolism Poly(ADP-ribose) Polymerases / metabolism Prostatic Neoplasms / metabolism, pathology* Proto-Oncogene Proteins c-bcl-2 / metabolism Staurosporine / pharmacology Tumor Cells, Cultured / drug effects, pathology Tumor Suppressor Protein p53 / metabolism bcl-X Protein |
| Chemical | |
Reg. No./Substance:
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0/Androgens; 0/Antineoplastic Agents; 0/BCL2L1 protein, human; 0/Cytochrome c Group; 0/Depsipeptides; 0/Enzyme Inhibitors; 0/Lactams; 0/Lactones; 0/Proto-Oncogene Proteins c-bcl-2; 0/Tumor Suppressor Protein p53; 0/bcl-X Protein; 0/cryptophycin 52; 62996-74-1/Staurosporine; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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