Pro-survival and pro-growth effects of stress-induced nitric oxide in a prostate cancer photodynamic therapy model

Reshma Bhowmick*, Albert W. Girotti

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    40 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)115-122
    Number of pages8
    JournalCancer Letters
    Volume343
    Issue number1
    DOIs
    StatePublished - Feb 1 2014

    Keywords

    • Nitric oxide
    • Nitric oxide synthase
    • Pancreatic cancer
    • Photodynamic therapy

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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