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1.
Oncogene ; 32(7): 920-9, 2013 Feb 14.
Article in English | MEDLINE | ID: mdl-22430213

ABSTRACT

p53 is essential for the cellular responses to DNA damage that help to maintain genomic stability. However, the great majority of human cancers undergo disruption of the p53-network. Identification and characterization of molecular components important in both p53-dependent and -independent apoptosis might be useful in developing novel therapies for cancers. In the complete absence of p53, cells treated with N-(phosphonacetyl)-L-aspartate (PALA) continue to synthesize DNA slowly and eventually progress through S-phase, suffering severe DNA damage that in turn triggers apoptosis, whereas cells with functional p53 undergo growth arrest. In this study, we investigated apoptotic signaling in response to PALA and the role of p53 expression in this pathway. We found that treatment of cells lacking p53 with PALA induced TAp73, Noxa and Bim and inactivation of these proteins with dominant-negative plasmids or small interfering RNAs significantly inhibited apoptosis, suggesting that PALA-induced apoptosis was mediated via TAp73-dependent expression of Noxa and Bim. However, PALA treatment inhibited the expression of ΔNp73 only in cells lacking p53 but not in cells expressing p53. In addition, PALA treatment inhibited Bcl-2, and overexpression of Bcl-2 significantly inhibited PALA-induced apoptosis. Moreover, expression of p53 in these cells protected them from PALA-induced apoptosis by activating p21, sustaining the expression of ΔNp73 and inhibiting the induction of Noxa and Bim. Taken together, our study identifies novel but opposing roles for the p53 and TAp73 in the induction of Noxa and Bim and regulation of apoptosis. Our data will help to develop strategies to eliminate cancer cells lacking p53 while protecting normal cells with wild-type p53.


Subject(s)
Apoptosis/drug effects , Aspartic Acid/analogs & derivatives , DNA-Binding Proteins/physiology , Neoplasms/drug therapy , Nuclear Proteins/physiology , Phosphonoacetic Acid/analogs & derivatives , Proto-Oncogene Proteins c-bcl-2/genetics , Tumor Suppressor Proteins/physiology , Antimetabolites, Antineoplastic/pharmacology , Antimetabolites, Antineoplastic/therapeutic use , Apoptosis/genetics , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Aspartic Acid/pharmacology , Aspartic Acid/therapeutic use , Bcl-2-Like Protein 11 , Cells, Cultured , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Drug Evaluation, Preclinical , Gene Expression Regulation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Phosphonoacetic Acid/pharmacology , Phosphonoacetic Acid/therapeutic use , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Tumor Protein p73 , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/physiology , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Up-Regulation/drug effects
2.
Leukemia ; 26(6): 1277-85, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22222598

ABSTRACT

Acute myeloid leukemia (AML) is the most common form of leukemia in adults. Unfortunately, the standard therapeutic agents used for this disease have high toxicities and poor efficacy. The one exception to these poor outcomes is the use of the retinoid, all-trans retinoic acid (ATRA), for a rare subtype of AML (APL). The use of the differentiation agent, ATRA, in combination with low-dose chemotherapy leads to the long-term survival and presumed cure of 75-85% of patients. Unfortunately ATRA has not been clinically useful for other subtypes of AML. Though many non-APL leukemic cells respond to ATRA, they require significantly higher concentrations of ATRA for effective differentiation. Here we show that the combination of ATRA with glycogen synthase kinase 3 (GSK3) inhibition significantly enhances ATRA-mediated AML differentiation and growth inhibition. These studies have revealed that ATRA's receptor, the retinoic acid receptor (RAR), is a novel target of GSK3 phosphorylation and that GSK3 can impact the expression and transcriptional activity of the RAR. Overall, our studies suggest the clinical potential of ATRA and GSK3 inhibition for AML and provide a mechanistic framework to explain the promising activity of this combination regimen.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Differentiation/drug effects , Glycogen Synthase Kinase 3/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Receptors, Retinoic Acid/genetics , Tretinoin/pharmacology , Animals , Blotting, Western , Cells, Cultured , Drug Synergism , Enzyme Inhibitors/pharmacology , Female , Glycogen Synthase Kinase 3/metabolism , Humans , Immunoprecipitation , Leukemia, Myeloid, Acute/metabolism , Luciferases/metabolism , Mice , Mice, Nude , Phosphorylation , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptors, Retinoic Acid/metabolism , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Transcriptional Activation/drug effects
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