Enhanced aggressiveness of bystander cells in an anti-tumor photodynamic therapy model: Role of nitric oxide produced by targeted cells. Free Radic Biol Med 2017 Jan;102:111-121
Date
11/26/2016Pubmed ID
27884704DOI
10.1016/j.freeradbiomed.2016.11.034Scopus ID
2-s2.0-85005965858 (requires institutional sign-in at Scopus site) 41 CitationsAbstract
The bystander effects of anti-cancer ionizing radiation have been widely studied, but far less is known about such effects in the case of non-ionizing photodynamic therapy (PDT). In the present study, we tested the hypothesis that photodynamically-stressed prostate cancer PC3 cells can elicit nitric oxide (NO)-mediated pro-growth/migration responses in non-stressed bystander cells. A novel approach was used whereby both cell populations existed on a culture dish, but made no physical contact with one other. Visible light irradiation of target cells sensitized with 5-aminolevulinic acid-induced protoporphyrin IX resulted in a striking upregulation of inducible nitric oxide synthase (iNOS) along with NO, the level of which increased after irradiation. Slower and less pronounced iNOS/NO upregulation was also observed in bystander cells. Activation of transcription factor NF-κB was implicated in iNOS induction in both targeted and bystander cells. Like surviving targeted cells, bystanders exhibited a significant increase in growth and migration rate, both responses being strongly attenuated by an iNOS inhibitor (1400W), a NO scavenger (cPTIO), or iNOS knockdown. Incubating bystander cells with conditioned medium from targeted cells failed to stimulate growth/migration, ruling out involvement of relatively long-lived stimulants. The following post-irradiation changes in pro-survival/pro-growth proteins were observed in bystander cells: upregulation of COX-2 and activation of protein kinases Akt and ERK1/2, NO again playing a key role. This is the first reported evidence for NO-enhanced bystander aggressiveness in the context of PDT. In the clinical setting, such effects could be averted through pharmacologic use of iNOS inhibitors as PDT adjuvants.
Author List
Bazak J, Fahey JM, Wawak K, Korytowski W, Girotti AWAuthor
Albert W. Girotti PhD Adjunct Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AmidinesApoptosis
Benzoates
Benzylamines
Bystander Effect
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cyclooxygenase 2
Enzyme Inhibitors
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Imidazoles
Light
Male
NF-kappa B
Nitric Oxide
Nitric Oxide Synthase Type II
Photochemotherapy
Prostatic Neoplasms
Protoporphyrins
