| Title | Signaling events in apoptotic photokilling of 5-aminolevulinic acid-treated tumor cells: Inhibitory effects of nitric oxide. | | Author(s) | Bhowmick R, Girotti AW | | Institution | Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA. | | Source | Free Radic Biol Med 2009 Jun 10. | | Abstract | Antitumor photodynamic therapy (PDT) employs a photosensitizing agent, molecular oxygen, and visible light to produce reactive oxygen species that can destroy tumor and tumor vasculature cells. NO produced by these cells could be pro-carcinogenic by inhibiting apoptosis and promoting angiogenesis and tumor growth. We recently showed that NO from a chemical donor or activated macrophages makes COH-BR1 breast tumor cells more resistant to photokilling sensitized by 5-aminolevulinic acid (ALA)-generated protoporphyrin IX (PpIX). Signaling events associated with this hyperresistance have now been examined. ALA-treated COH-BR1 cells containing mitochondria-localized PpIX died mainly by apoptosis after being irradiated. Underlying redox signaling associated with MAP kinase (ERK1/2, p38, JUN) phosphorylation-activation and heme oxygenase-1 (HO-1) upregulation was studied using immunoprecipitation and Western blot methodology. ALA/light treatment resulted in activation of pro-apoptotic JNK and p38alpha, and deactivation of pro-survival p38beta and ERK1/2. Involvement of both JNK and p38 in apoptosis was established by using a specific inhibitor for each. Spermine NONOate-derived NO, introduced immediately before irradiation, provided substantial protection against apoptosis. This was accompanied by greater HO-1 induction and strong inhibition of each MAP kinase effect seen in the absence of NO. Downstream of JNK and p38alpha activation, a marked upregulation/activation of pro-apoptotic Bax and Bid was observed along with down-regulation of anti-apoptotic Bcl-xL, each response being reversed by NO. These findings provide new insights into signaling activity associated with the intrinsic apoptotic pathway in ALA-PDT and how this activity can be modulated by NO. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19524035 |
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