Pro-survival and pro-growth effects of stress-induced nitric oxide in a prostate cancer photodynamic therapy model.
We discovered recently that human breast cancer cells subjected to photodynamic therapy (PDT)-like oxidative stress localized in mitochondria rapidly upregulated nitric oxide synthase-2 (NOS2) and nitric oxide (NO), which increased resistance to apoptotic photokilling. In this study, we asked whether human prostate cancer PC-3 cells would exploit NOS2/NO similarly and, if so, how proliferation of surviving cells might be affected. Irradiation of photosensitized PC-3 cells resulted in a rapid (<1 h), robust (~12-fold), and prolonged (∼20 h) post-irradiation upregulation of NOS2. Caspase-3/7 activation and apoptosis were stimulated by NOS2 inhibitors and a NO scavenger, implying that induced NO was acting cytoprotectively. Cyclic GMP involvement was ruled out, whereas suppression of pro-apoptotic JNK and p38 MAPK activation was clearly implicated. Cells surviving photostress grew back ~2-times faster than controls. NOS2 inhibition prevented this and the large increase in cell cycle S-phase occupancy observed after irradiation. Thus, photostress upregulation of NOS/NO elicited both a pro-survival and pro-growth response, both of which could compromise clinical PDT efficacy unless suppressed, e.g. by pharmacological intervention with a NOS2 inhibitor.
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: rbhowmic@gmail.com.
Reshma
R
Bhowmick
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: agirotti@mcw.edu.
Albert W
AW
Girotti
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004789:Enzyme Activation; D005609:Free Radicals; D006801:Humans; D008027:Light; D020935:MAP Kinase Signaling System; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010778:Photochemotherapy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000628:therapy*
D005609:Free Radicals; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7
Nitric oxide; Nitric oxide synthase; Pancreatic cancer; Photodynamic therapy