aphidicolin and Prostatic-Neoplasms

aphidicolin has been researched along with Prostatic-Neoplasms* in 3 studies

Other Studies

3 other study(ies) available for aphidicolin and Prostatic-Neoplasms

ArticleYear
Indirect participation of Hsp90 in the regulation of the cyclin E turnover.
    Biochemical pharmacology, 2009, Jan-15, Volume: 77, Issue:2

    Cyclin E is the Cdk2-regulatory subunit required for the initiation of DNA replication at the G1/S transition. It accumulates in late G1 phase and gets rapidly degraded by the ubiquitin/proteasome pathway during S phase. The degradation of cyclin E is a consequence of its phosphorylation and subsequent isomerization by the peptidyl-prolyl isomerase Pin1. We show that in the colon cancer cells HT-29 the inhibition of the chaperone function of Hsp90 by geldanamycin (GA) enhances the ubiquitinylation of cyclin E and triggers active degradation via the proteasome pathway. As Hsp90 forms multiprotein complexes with and regulates the function and cell contents of numerous signaling proteins, this observation suggests a direct interaction between Hsp90 and cyclin E. However, experiments using cell lysate fractionation did not reveal the presence of complexes containing both Hsp90 and cyclin E. Coupled transcription/translation experiments also failed to detect the formation of complexes between newly synthesized cyclin E and Hsp90. We conclude that Hsp90 can regulate the degradation of cellular proteins without binding to them, by an indirect mechanism. This conclusion postulates a new category of proteins that are affected by the inactivation of Hsp90. Our observations do not support the possible involvement of a PPIase in this indirect mechanism. Besides, we did not observe active geldanamycin-dependent degradation of cyclin E in the prostate cancer-derived cell line DU-145, indicating that the Hsp90-dependent stabilization of cyclin E requires specific regulatory mechanism which may be lost in certain types of cancer cells.

    Topics: Antibiotics, Antineoplastic; Aphidicolin; Benzoquinones; Cell Cycle; Cell Line, Tumor; Colonic Neoplasms; Cyclin E; DNA Replication; Homeostasis; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Male; Neoplasm Proteins; Prostatic Neoplasms; Protein Biosynthesis; Transcription, Genetic; Ubiquitin

2009
S-phase checkpoints regulate Apo2 ligand/TRAIL and CPT-11-induced apoptosis of prostate cancer cells.
    Molecular cancer therapeutics, 2007, Volume: 6, Issue:4

    As S-phase checkpoints play critical roles in maintaining genomic integrity and replicating the human genome correctly, understanding the molecular mechanism by which they regulate the therapeutic response is of great interest. Previously, we reported that the cytotoxic effect of a zinc-bound form of Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL), which is currently evaluated in clinical trials, in combination with low-dose CPT-11, induces apoptosis of C4-2 human prostate cancer cells and tissues. Here, we show that apoptosis, induced synergistically by this combination treatment, was associated with accumulation of cells in early S phase, indicated by cell cycle analyses, increased proliferating cell nuclear antigen, and Chk2-Thr(68) phosphorylation in tumors xenografted in mice. The combination treatment induced an S-phase checkpoint response through activation of Chk2 and Chk1 by the ataxia telangiectasia mutated and ataxia telangiectasia mutated and Rad3 related kinases, leading to phosphorylation and decreased Cdc25A levels. Cdc25A-dependent regulation of cyclin-dependent kinase 2 (Cdk2) and changes in association of p21(WAF1/CIP1) and hSpy1 with Cdk2 resulted in inhibition of Cdk2-associated kinase activity. Knockdown of ataxia telangiectasia mutated/Chk2 and ataxia telangiectasia mutated and Rad3 related/Chk1 by small inhibitory RNAs abrogated the S-phase checkpoint and accelerated apoptosis, resulting in caspase-3 activation and poly(ADP-ribose) polymerase 1 cleavage following combination treatment. Thus, Apo2L/TRAIL + CPT-11 treatment-induced apoptosis is regulated through an S-phase checkpoint controlled by the Chk2-Cdc25A and Chk1-Cdc25A pathways and inhibition of Cdk2-associated kinase activity. Low-dose CPT-11 and aphidicolin increased the proportion of S-phase cells and sensitized cells to Apo2L/TRAIL, by inducing phosphatidylserine externalization, caspase activation, and poly(ADP-ribose) polymerase 1 cleavage. Combinations with S-phase arrest-inducing chemotherapeutic drugs may represent promising avenues for clinical development of Apo2L/TRAIL.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Aphidicolin; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Camptothecin; Cell Cycle Proteins; Cell Line, Tumor; Checkpoint Kinase 1; Checkpoint Kinase 2; DNA-Binding Proteins; Down-Regulation; Drug Synergism; Enzyme Activation; Humans; Irinotecan; Ligands; Male; Mice; Prostatic Neoplasms; Protein Kinases; Protein Serine-Threonine Kinases; Receptors, TNF-Related Apoptosis-Inducing Ligand; S Phase; TNF-Related Apoptosis-Inducing Ligand; Transplantation, Heterologous; Tumor Suppressor Proteins

2007
Drug-induced apoptosis is not necessarily dependent on macromolecular synthesis or proliferation in the p53-negative human prostate cancer cell line PC-3.
    Cancer research, 1995, May-15, Volume: 55, Issue:10

    The propensity of a cell to undergo apoptosis has been proposed to be a determinant for chemotherapy sensitivity that is not directly dependent on specific drug-target interactions. Androgen-independent prostate cancer is typically refractory to cytotoxic drugs, and we tested whether this is due to a loss of the ability to undergo apoptosis. Exposure of the hormone-insensitive and p53-negative human prostate carcinoma cell line PC-3 to 22 microM cisplatin, 1 microM camptothecin, 10 microM tenoposide, 135 nM vincristine, or 10 microM lovastatin for 72 h caused cell death, internucleosomal DNA fragmentation, and morphological changes typical for apoptosis. One microM cycloheximide prevented anticancer drug-induced apoptosis, whereas high concentration (1 mM) of cycloheximide alone induced apoptosis, indicating that protein synthesis was not needed for these cells to undergo apoptosis. Since cycloheximide affected DNA synthesis and proliferation of PC-3 cells, we tested whether the DNA polymerase inhibitor aphidicolin could also suppress drug-induced apoptosis. In contrast to cycloheximide, aphidicolin inhibited only vincristine-induced apoptosis. Cycloheximide prevented drug-induced changes in cell cycle distribution except for vincristine, while aphidicolin led to an accumulation of cells at the G1-S border independent of the drug used. These data indicate that macromolecular synthesis, active cell cycling, and p53 expression are not required for apoptosis to proceed in this system.

    Topics: Antineoplastic Agents; Aphidicolin; Apoptosis; Cell Cycle; Cell Division; Cycloheximide; DNA, Neoplasm; Humans; Lovastatin; Male; Microscopy, Electron; Nucleosomes; Prostatic Neoplasms; Tumor Cells, Cultured

1995
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