PARP-1 inhibition-induced activation of PI-3-kinase-Akt pathway promotes resistance to taxol.
PARP inhibitors combined with DNA-damage inducing cytostatic agents can lead to effective tumor therapy. However, inhibition of poly(ADP-ribose) polymerase (PARP-1; EC 2.4.2.30) induces the activation of PI-3-kinase-Akt pathway, which can counteract the effectiveness of this therapy. To understand the role of Akt activation in the combined use of cytostatic agent and PARP inhibition, we used taxol (paclitaxel) as an antineoplastic agent, which targets microtubules and up-regulates mitochondrial ROS production, together with (i) pharmacological inhibition (PJ-34), (ii) siRNA knock-down and (iii) transdominant expression of the DNA binding domain of PARP-1. In all cases, PARP-1 inhibition leads to suppressed poly-ADP-ribosylation of nuclear proteins, prevention of NAD(+) depletion and significant resistance against taxol induced caspase-3 activation and apoptotic cell death. Paclitaxel induced a moderate increase in Akt activation, which was significantly augmented by PARP inhibition, suggesting that PARP inhibition-induced Akt activation could be responsible for the cytostatic resistance. When activation of the PI-3-kinase-Akt pathway was prevented by LY-294002 or Akt Inhibitor IV, the cytoprotective effect of PARP inhibition was significantly diminished showing that the activation of PI-3-kinase-Akt cascade had significantly contributed to the cytostatic resistance. Our study demonstrates that drug-induced drug resistance can be responsible for the reduced efficacy of antitumor treatment. Although inhibition of PARP-1 can promote cell death in tumor cells by the inhibition of DNA repair, PARP-inhibition promoted activation of the PI-3-kinase-Akt pathway can counteract this facilitating effect, and can cause cytostatic resistance. We suggest augmenting PARP inhibition by the inhibition of the PI-3-kinase-Akt pathway for antitumor therapy.
Department of Urology, Faculty of Medicine University of Pecs, Pecs, Hungary.
Arpad
A
Szanto
Eva E
EE
Hellebrand
Zita
Z
Bognar
Zsuzsanna
Z
Tucsek
Aliz
A
Szabo
Ferenc
F
Gallyas
Balazs
B
Sumegi
Gabor
G
Varbiro
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D045304:Cytochromes c / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D045304:Cytochromes c; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D017239:Paclitaxel