Pro-survival and pro-growth effects of stress-induced nitric oxide in a prostate cancer photodynamic therapy model. Cancer Lett 2014 Feb 01;343(1):115-22
Date
10/02/2013Pubmed ID
24080338Pubmed Central ID
PMC3874260DOI
10.1016/j.canlet.2013.09.025Scopus ID
2-s2.0-84890859657 (requires institutional sign-in at Scopus site) 63 CitationsAbstract
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.
Author List
Bhowmick R, Girotti AWAuthor
Albert Girotti PhD, MS Emeritus Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ApoptosisCaspase 3
Caspase 7
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Cell Survival
Enzyme Activation
Free Radicals
Humans
Light
MAP Kinase Signaling System
Male
Nitric Oxide
Nitric Oxide Synthase Type II
Photochemotherapy
Prostatic Neoplasms
