Radiation-induced PARP activation is enhanced through EGFR-ERK signaling.
We examined the impact of EGFR-ERK signaling on poly (ADP-ribose) polymerase (PARP) activation following ionizing irradiation of human prostate cancer (PCa) cell lines displaying marked differences in ERK dependence. PARP activation was indicated by the appearance of polyADP-ribose, the incorporation of P32-labelled NADH, and by cellular NADH. EGFR-ERK signaling was manipulated through ligand activation or signal interruption using the tyrphostin AG1478, or MEK inhibitor PD 184352. EGF activation of ERK prior to irradiation was associated with a marked increase in PARP activation and decreased survival in both cell lines. Prior inactivation of PARP protected both cell lines from the initial decrease in NAD+ and improved the survival of LNCaP cells following combined EGF and IR treatment. MEK inhibitor PD 184352 also reduced PARP activation and improved LNCaP survival following EGF and IR treatment. These data imply that PARP activation following exposure to ionizing radiation is enhanced through EGFR-ERK signaling.
Hagan
Michael P
MP
Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23298, USA. mhagan@mcvh-vcu.edu
Yacoub
Adly
A
Dent
Paul
P
D016923:Cell Death; D045744:Cell Line, Tumor / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D009243:NAD / Q000378:metabolism; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing
D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D009243:NAD; D011065:Poly(ADP-ribose) Polymerases; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; C484007:NMNAT1 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase