title: Dual roles of PARP-1 promote cancer growth and progression.
abstract: PARP-1 is an abundant nuclear enzyme that modifies substrates by poly(ADP-ribose)-ylation. PARP-1 has well-described functions in DNA damage repair and also functions as a context-specific regulator of transcription factors. With multiple models, data show that PARP-1 elicits protumorigenic effects in androgen receptor (AR)-positive prostate cancer cells, in both the presence and absence of genotoxic insult. Mechanistically, PARP-1 is recruited to sites of AR function, therein promoting AR occupancy and AR function. It was further confirmed in genetically defined systems that PARP-1 supports AR transcriptional function, and that in models of advanced prostate cancer, PARP-1 enzymatic activity is enhanced, further linking PARP-1 to AR activity and disease progression. In vivo analyses show that PARP-1 activity is required for AR function in xenograft tumors, as well as tumor cell growth in vivo and generation and maintenance of castration resistance. Finally, in a novel explant system of primary human tumors, targeting PARP-1 potently suppresses tumor cell proliferation. Collectively, these studies identify novel functions of PARP-1 in promoting disease progression, and ultimately suggest that the dual functions of PARP-1 can be targeted in human prostate cancer to suppress tumor growth and progression to castration resistance.
  
  
  CONCLUSIONS
  These studies introduce a paradigm shift with regard to PARP-1 function in human malignancy, and suggest that the dual functions of PARP-1 in DNA damage repair and transcription factor regulation can be leveraged to suppress pathways critical for promalignant phenotypes in prostate cancer cells by modulation of the DNA damage response and hormone signaling pathways. The combined studies highlight the importance of dual PARP-1 function in malignancy and provide the basis for therapeutic targeting.
authors.affiliation: Departments of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schiewer
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Goodwin
authors.forename: Sumin
authors.initials: S
authors.lastname: Han
authors.forename: J Chad
authors.initials: JC
authors.lastname: Brenner
authors.forename: Michael A
authors.initials: MA
authors.lastname: Augello
authors.forename: Jeffry L
authors.initials: JL
authors.lastname: Dean
authors.forename: Fengzhi
authors.initials: F
authors.lastname: Liu
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Planck
authors.forename: Preethi
authors.initials: P
authors.lastname: Ravindranathan
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Peter
authors.initials: P
authors.lastname: McCue
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Gomella
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brody
authors.forename: John M
authors.initials: JM
authors.lastname: Pascal
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Centenera
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Butler
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D018450:Disease Progression; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D002843:Chromatin; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011944:Receptors, Androgen; C521013:veliparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases