ADP-ribosyltransferases(ARTs)regulate key processes in cancer,including DNA repair,transcription,immune responses,and treatment resistance.The clostridial toxin-like ADP-ribosyltransferase(ARTC)family and the diphther...ADP-ribosyltransferases(ARTs)regulate key processes in cancer,including DNA repair,transcription,immune responses,and treatment resistance.The clostridial toxin-like ADP-ribosyltransferase(ARTC)family and the diphtheria toxin-like ADP-ribosyltransferase(ARTD)family play a crucial role in genomic stability by modification of proteins either with mono(ADP-ribosyl)ation(MARylation)or poly(ADP-ribosyl)ation(PARylation).These ARTs are promising therapeutic targets and could serve as biomarkers in cancer management.This review explores the roles of these enzymes and current knowledge on specific inhibitors.A literature search was conducted in PubMed and Google Scholar to identify studies published between 1992 and 2025 on ADP-ribosyltransferases and their roles in cancer.Among ARTC family,ART1 and ART3 modulate the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathway,influencing angiogenesis,tumor growth,and immune evasion via cluster of differentiation 8+(CD8+)T-cell apoptosis.Within the ARTD family,poly(ADP-ribose)polymerase(PARP)1 and PARP2 are activated by DNA single-strand breaks and are clinically validated targets in cancers with homologous recombination deficiency,such as breast cancer susceptibility genes 1/2(BRCA1/2)-mutated breast cancer.Their inhibition exemplifies synthetic lethality and has shown clinical efficacy.Four PARP inhibitors,olaparib,niraparib,rucaparib,are approved by the Food and Drug Administration(FDA)approved.Despite these advances,selective inhibitors for ARTs remain underexplored.Ongoing research focuses on overcoming PARP inhibitor resistance,improving biomarker-driven patient selection,and expanding therapeutic strategies that target ART-related pathways.展开更多
Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.How...Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.However,relatively few studies have explored the impact of post-translational modifications(PTM)on OC progression,which is essential for uncovering new therapeutic targets.This study aimed to systematically identify the key PTM types involved in OCprogression,and to explore and evaluate their translational potential as therapeutic targets.Methods:First,we utilized multiple general PTM antibodies to compare gross PTM levels between normal ovarian and OC tissues from clinical females.After identifying lactylation as the PTM with the most significant differences,we selected representative samples for label-free mass spectrometry to identify specific lactylation sites.Next,we transfected A2780(OC)cells with either wild-type(WT)or mutant(K192A[Q])poly(ADP-ribose)polymerase 1(PARP1)conjugated to enhanced green fluorescent protein(EGFP)with a StrepⅡpeptide tag and assessed various cellular indexes related to cell proliferation(clonogenicity assay),migration(scratch wound healing assay),and reactive oxygen species levels.Results:Pan-lactylation was significantly upregulated in clinical OC samples,with PARP1 lactylation at K192 being one of the most common modifications.The growth and migration of A2780 cells were markedly suppressed by overexpressing PARP1-WT but not mutant PARP1.Overexpressing PARP1 significantly downregulated the phosphorylation of extracellular signal-regulated kinases 1/2(ERK1/2).Conclusion:This study uncovered a novel PTM of PARP1 in OC,lactylation,and demonstrated that lactylation at K192 is crucial in regulating OC cell growth and migration via the ERK1/2 pathway.Further investigations are required to elucidate the broader functional implications of PARP1 lactylation and its therapeutic potential.展开更多
文摘ADP-ribosyltransferases(ARTs)regulate key processes in cancer,including DNA repair,transcription,immune responses,and treatment resistance.The clostridial toxin-like ADP-ribosyltransferase(ARTC)family and the diphtheria toxin-like ADP-ribosyltransferase(ARTD)family play a crucial role in genomic stability by modification of proteins either with mono(ADP-ribosyl)ation(MARylation)or poly(ADP-ribosyl)ation(PARylation).These ARTs are promising therapeutic targets and could serve as biomarkers in cancer management.This review explores the roles of these enzymes and current knowledge on specific inhibitors.A literature search was conducted in PubMed and Google Scholar to identify studies published between 1992 and 2025 on ADP-ribosyltransferases and their roles in cancer.Among ARTC family,ART1 and ART3 modulate the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathway,influencing angiogenesis,tumor growth,and immune evasion via cluster of differentiation 8+(CD8+)T-cell apoptosis.Within the ARTD family,poly(ADP-ribose)polymerase(PARP)1 and PARP2 are activated by DNA single-strand breaks and are clinically validated targets in cancers with homologous recombination deficiency,such as breast cancer susceptibility genes 1/2(BRCA1/2)-mutated breast cancer.Their inhibition exemplifies synthetic lethality and has shown clinical efficacy.Four PARP inhibitors,olaparib,niraparib,rucaparib,are approved by the Food and Drug Administration(FDA)approved.Despite these advances,selective inhibitors for ARTs remain underexplored.Ongoing research focuses on overcoming PARP inhibitor resistance,improving biomarker-driven patient selection,and expanding therapeutic strategies that target ART-related pathways.
文摘Objective:Ovarian cancer(OC)ranks among the leading causes of mortality among the female cancers worldwide.Numerous studies have explored the development and progression of OC at multiple genetic regulatory levels.However,relatively few studies have explored the impact of post-translational modifications(PTM)on OC progression,which is essential for uncovering new therapeutic targets.This study aimed to systematically identify the key PTM types involved in OCprogression,and to explore and evaluate their translational potential as therapeutic targets.Methods:First,we utilized multiple general PTM antibodies to compare gross PTM levels between normal ovarian and OC tissues from clinical females.After identifying lactylation as the PTM with the most significant differences,we selected representative samples for label-free mass spectrometry to identify specific lactylation sites.Next,we transfected A2780(OC)cells with either wild-type(WT)or mutant(K192A[Q])poly(ADP-ribose)polymerase 1(PARP1)conjugated to enhanced green fluorescent protein(EGFP)with a StrepⅡpeptide tag and assessed various cellular indexes related to cell proliferation(clonogenicity assay),migration(scratch wound healing assay),and reactive oxygen species levels.Results:Pan-lactylation was significantly upregulated in clinical OC samples,with PARP1 lactylation at K192 being one of the most common modifications.The growth and migration of A2780 cells were markedly suppressed by overexpressing PARP1-WT but not mutant PARP1.Overexpressing PARP1 significantly downregulated the phosphorylation of extracellular signal-regulated kinases 1/2(ERK1/2).Conclusion:This study uncovered a novel PTM of PARP1 in OC,lactylation,and demonstrated that lactylation at K192 is crucial in regulating OC cell growth and migration via the ERK1/2 pathway.Further investigations are required to elucidate the broader functional implications of PARP1 lactylation and its therapeutic potential.
