Abstract
Treatment of p53-deficient PC-3 human prostate carcinoma cells with nanomolar concentrations of bis-anthracycline WP631 induced changes in gene expression, which resulted in G2/M cell cycle arrest, autophagy and cell death. The presence of 2-deoxy-D-glucose (2-DG), which induces metabolic stress and autophagy, enhanced the antiproliferative effects of WP631. Changes induced by WP631, 2-DG, or co-treatments with both compounds, in the expression of a variety of genes involved in autophagy and apoptosis were quantified by real-time PCR. They were consistent with a raise in autophagy followed by cell death. Some cells dying from G2/M phase showed features of necrosis like early changes in membrane permeability, while others were dying by apoptosis that occurred in presence of little caspase-3 activity. Our results indicate that WP631 is not only an antiproliferative agent acting on gene transcription, but it can also induce autophagy regardless of the presence of other pro-autophagy stimuli. The development of autophagy seemed to improve the cytotoxicity of WP631 in PC-3 cells. Our results indicate that autophagy would enhance the activity of DNA-binding drugs like WP631 that are potent inhibitors of gene transcription.
Keywords:
PC-3 cells; Sp1; WP631; autophagy; cell death.
© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Antibiotics, Antineoplastic / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Autophagy / drug effects*
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Autophagy / genetics
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Beclin-1
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Daunorubicin / analogs & derivatives*
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Daunorubicin / pharmacology
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Deoxyglucose / pharmacology
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Dose-Response Relationship, Drug
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Drug Synergism
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Flow Cytometry
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G2 Phase Cell Cycle Checkpoints / drug effects
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G2 Phase Cell Cycle Checkpoints / genetics
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Gene Expression / drug effects
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Humans
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Reverse Transcriptase Polymerase Chain Reaction
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Sequestosome-1 Protein
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Time Factors
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Tumor Suppressor Protein p53 / deficiency*
Substances
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Adaptor Proteins, Signal Transducing
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Antibiotics, Antineoplastic
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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Beclin-1
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MAP1LC3A protein, human
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Membrane Proteins
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Microtubule-Associated Proteins
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SQSTM1 protein, human
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Sequestosome-1 Protein
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Tumor Suppressor Protein p53
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WP 631
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Deoxyglucose
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Daunorubicin
Associated data
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RefSeq/NM_000633
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RefSeq/NM_001165412
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RefSeq/NM_002046
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RefSeq/NM_002467
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RefSeq/NM_003766
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RefSeq/NM_004324
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RefSeq/NM_004346
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RefSeq/NM_013325
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RefSeq/NM_022488
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RefSeq/NM_032514
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RefSeq/NM_138473