p21(WAF1) modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia.

Abstract

p21(WAF1) is a well-characterized mediator of cell cycle arrest and may also modulate chemotherapy-induced cell death. The role of p21(WAF1) in drug-induced cell cycle arrest and apoptosis of acute lymphoblastic leukemia (ALL) cells was investigated using p53-functional patient-derived xenografts (PDXs), in which p21(WAF1) was epigenetically silenced in T-cell ALL (T-ALL), but not in B-cell precursor (BCP)-ALL PDXs. Upon exposure to diverse cytotoxic drugs, T-ALL PDX cells exhibited markedly increased caspase-3/7 activity and phosphatidylserine (PS) externalization on the plasma membrane compared with BCP-ALL cells. Despite dramatic differences in apoptotic characteristics between T-ALL and BCP-ALL PDXs, both ALL subtypes exhibited similar cell death kinetics and were equally sensitive to p53-inducing drugs in vitro, although T-ALL PDXs were significantly more sensitive to the histone deacetylase inhibitor vorinostat. Transient siRNA suppression of p21(WAF1) in the BCP-ALL 697 cell line resulted in a moderate depletion of the cell fraction in G1 phase and marked increase in PS externalization following exposure to etoposide. Furthermore, stable lentiviral p21(WAF1) silencing in the BCP-ALL Nalm-6 cell line accelerated PS externalization and cell death following exposure to etoposide and vorinostat, supporting previous findings. Finally, the Sp1 inhibitor, terameprocol, inhibited p21(WAF1) expression in Nalm-6 cells exposed to vorinostat and also partially augmented vorinostat-induced cell death. Taken together, these findings demonstrate that p21(WAF1) regulates the early stages of drug-induced apoptosis in ALL cells and significantly modulates their sensitivity to vorinostat.

• Authors: Carwyn Davies, Linda A Hogarth, Karen L Mackenzie, Andrew G Hall, Richard B Lock
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 14 Issue 22 Pg. 3602-12 ( 2015) ISSN: 1551-4005 [Electronic] United States
• PMID: 26506264 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Phosphatidylserines
• RNA, Small Interfering
• Sp1 Transcription Factor
• SP1 protein, human
• Tumor Suppressor Protein p53
• terameprocol
• Vorinostat
• Etoposide
• Masoprocol
• CASP3 protein, human
• CASP7 protein, human
• Caspase 3
• Caspase 7

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• B-Lymphocytes (drug effects, metabolism, pathology)
• Caspase 3 (genetics, metabolism)
• Caspase 7 (genetics, metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21 (antagonists & inhibitors, genetics, metabolism)
• Etoposide (pharmacology)
• Gene Expression Regulation, Leukemic
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Masoprocol (analogs & derivatives, pharmacology)
• Phosphatidylserines (metabolism)
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism, pathology)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism, pathology)
• RNA, Small Interfering (genetics, metabolism)
• Signal Transduction
• Sp1 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• T-Lymphocytes (drug effects, metabolism, pathology)
• Transcription, Genetic
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Vorinostat