title: N-(phosphonacetyl)-L-aspartate induces TAp73-dependent apoptosis by modulating multiple Bcl-2 proteins: potential for cancer therapy.
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.
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: A R M
authors.initials: AR
authors.lastname: Ruhul Amin
authors.forename: V S
authors.initials: VS
authors.lastname: Thakur
authors.forename: K
authors.initials: K
authors.lastname: Gupta
authors.forename: M K
authors.initials: MK
authors.lastname: Agarwal
authors.forename: D N
authors.initials: DN
authors.lastname: Wald
authors.forename: D M
authors.initials: DM
authors.lastname: Shin
authors.forename: M L
authors.initials: ML
authors.lastname: Agarwal
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000072224:Bcl-2-Like Protein 11; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D001224:Aspartic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid