Differentiative pathway activated by 3-aminobenzamide, an inhibitor of PARP, in human osteosarcoma MG-63 cells.
This study describes the molecular mechanism by which treatment with 3-AB, a potent inhibitor of PARP, allows human osteosarcoma MG-63 cells to restrict growth and enter differentiation. Our findings show that in MG-63 cells, aberrant gene expression keeps Rb protein constitutively inactivated through hyperphosphorylation and this promotes uncontrolled proliferation of the cells. After 3-AB-treatment, the poly(ADP-ribosyl)ation of nuclear proteins markedly decreases and this results in an increase in both the hypophosphorylated active form of Rb and pRb/E2F complexes. These effects are accompanied by G1 arrest, downregulation of gene products required for proliferation (cyclin D1, beta-catenin, c-Jun, c-Myc and Id2) and upregulation of those implicated in the osteoblastic differentiation (p21/Waf1, osteopontin, osteocalcin, type I collagen, N-cadherins and alkaline phosphatase). Our study suggests that use of PARP inhibitors may induce a remodeling of chromatin with the reprogramming of gene expression and the activation of differentiation.
De Blasio
A
A
Dipartimento di Biologia Cellulare e dello Sviluppo, Sezione di Biochimica, Università di Palermo, Policlinico, via del Vespro 129, 90127 Palermo, Italy.
Messina
C
C
Santulli
A
A
Mangano
V
V
Di Leonardo
E
E
D'Anneo
A
A
Tesoriere
G
G
Vento
R
R
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D001483:Base Sequence; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D012516:Osteosarcoma / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016160:Retinoblastoma Protein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism
D001549:Benzamides; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D000246:Adenosine Diphosphate Ribose; C025160:3-aminobenzamide