X-linked inhibitor of apoptosis protein inhibition induces apoptosis and enhances chemotherapy sensitivity in human prostate cancer cells.

Abstract

Androgen-insensitive prostate cancer cells are highly resistant to several chemotherapeutic drugs and are characterized by the appearance of apoptosis-resistant cells. In this study, we identified the critical role of X-linked inhibitor of apoptosis protein (XIAP), a potent antiapoptotic factor, in conferring chemotherapy resistance in an androgen-insensitive DU145 human prostate cancer cell line. Results reveal that DU145 cells were highly resistant to cisplatin, but this resistance was overridden when the cells were treated for a prolonged time (>96 hours) with cisplatin (IC(50) = 27.5 to 35.5 micromol/L). A decrease in levels of XIAP and Akt/phospho-Akt and an increase in caspase-3 activity were identified to be key factors in cisplatin sensitivity (40% to 55% decrease in cell viability) at later time points. In contrast, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment caused a 40% to 50% decrease in cell viability within 6 hours (IC(50) = 135 to 145 ng/mL). However, increasing concentrations or prolonged treatment with TRAIL did not change drug potency. A significant increase in caspase-3 activity was observed with TRAIL treatment with no apparent change in XIAP levels. Specific inhibition of XIAP expression using an antisense XIAP phosphorodiamidate morpholino oligomer induced apoptosis and increased caspase-3 activity. Combination of cisplatin with XIAP antisense potentiated cisplatin sensitivity by decreasing the IC(50) from >200 micromol/L with cisplatin alone to 9 to 20 micromol/L and decreasing incubation time required for activity from 96 to 24 hours. Similarly, TRAIL in combination with XIAP antisense phosphorodiamidate morpholino oligomer enhanced TRAIL potency by 12- to 13-fold. In conclusion, abrogation of XIAP expression is essential for therapeutic apoptosis and enhanced chemotherapy sensitization in androgen-refractory prostate cancer cells.

• Authors: Adams Amantana, Carla A London, Patrick L Iversen, Gayathri R Devi
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 3 Issue 6 Pg. 699-707 (Jun 2004) ISSN: 1535-7163 [Print] United States
• PMID: 15210856 (Publication Type: Journal Article)

Chemical References

• Apoptosis Regulatory Proteins
• Membrane Glycoproteins
• Morpholines
• Morpholinos
• Oligodeoxyribonucleotides, Antisense
• Proteins
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• CASP3 protein, human
• Caspase 3
• Caspases
• Cisplatin

Topics

• Apoptosis (drug effects, genetics)
• Apoptosis Regulatory Proteins
• Caspase 3
• Caspases (metabolism)
• Cell Line, Tumor
• Cisplatin (agonists, pharmacology)
• Drug Resistance, Neoplasm
• Enzyme Activation
• Gene Expression Regulation, Neoplastic
• HeLa Cells
• Humans
• Male
• Membrane Glycoproteins (agonists, metabolism)
• Morpholines (pharmacology)
• Morpholinos
• Oligodeoxyribonucleotides, Antisense (genetics, metabolism)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Proteins (antagonists & inhibitors, genetics, metabolism)
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Necrosis Factor-alpha (agonists, metabolism)
• X-Linked Inhibitor of Apoptosis Protein