Autophagy modulates the effects of bis-anthracycline WP631 on p53-deficient prostate cancer cells.

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.

• Authors: Sylvia Mansilla, Carolina Vizcaíno, Maria A Rodríguez-Sánchez, Waldemar Priebe, José Portugal
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 19 Issue 4 Pg. 786-98 (Apr 2015) ISSN: 1582-4934 [Electronic] England
• PMID: 25689150 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antibiotics, Antineoplastic
• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• MAP1LC3A protein, human
• Membrane Proteins
• Microtubule-Associated Proteins
• SQSTM1 protein, human
• Sequestosome-1 Protein
• Tumor Suppressor Protein p53
• WP 631
• Deoxyglucose
• Daunorubicin

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis (drug effects, genetics)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy (drug effects, genetics)
• Beclin-1
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Daunorubicin (analogs & derivatives, pharmacology)
• Deoxyglucose (pharmacology)
• Dose-Response Relationship, Drug
• Drug Synergism
• Flow Cytometry
• G2 Phase Cell Cycle Checkpoints (drug effects, genetics)
• Gene Expression (drug effects)
• Humans
• Male
• Membrane Proteins (genetics, metabolism)
• Microtubule-Associated Proteins (genetics, metabolism)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• Sequestosome-1 Protein
• Time Factors
• Tumor Suppressor Protein p53 (deficiency)