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Cited by 67Photodynamic Therapy Research StudiesCell death mechanisms and regulationNanoplatforms for cancer theranostics

Cytoprotective Signaling Associated with Nitric Oxide Upregulation in Tumor Cells Subjected to Photodynamic Therapy-like Oxidative Stress

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Bhowmick, Reshma, Girotti, Albert W.·2013·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2012.12.005PMC PMC3594367
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Abstract

Photodynamic therapy (PDT) employs photoexcitation of a sensitizer to generate tumor-eradicating reactive oxygen species. We recently showed that irradiating breast cancer COH-BR1 cells after treating with 5-aminolevulinic acid (ALA, a pro-sensitizer) resulted in rapid upregulation of inducible nitric oxide (NO) synthase (iNOS). Apoptotic cell killing was strongly enhanced by an iNOS inhibitor (1400W), iNOS knockdown (kd), or a NO scavenger, suggesting that NO was acting cytoprotectively. Stress signaling associated with these effects was examined in this study. ALA/light-stressed COH-BR1 cells, and also breast adenocarcinoma MDA-MB-231 cells, mounted an iNOS/NO-dependent resistance to apoptosis that proved to be cGMP-independent. Immunocytochemistry and subcellular Western analysis of photostressed COH-BR1 cells revealed a cytosol-to-nucleus translocation of NF-κB which was negated by the NF-κB activation inhibitor Bay11. Bay11 also enhanced apoptosis and prevented iNOS induction, consistent with NF-κB involvement in the latter. JNK and p38 MAP kinase inhibitors suppressed apoptosis, implicating these kinases in death signaling. Post-irradiation extent and duration of JNK and p38 phosphorylation were dramatically elevated by 1400 W or iNOS-kd, suggesting that these activations were suppressed by NO. Regarding pro-survival stress signaling, rapid activation of Akt was unaffected by 1400 W, but prevented by Wortmannin, which also enhanced apoptosis. Thus, a link between upstream Akt activation and iNOS induction was apparent. Furthermore, p53 protein expression under photostress was elevated by iNOS-kd, whereas robust Survivin induction was abolished, consistent with p53 and Survivin being negatively and positively regulated by NO, respectively. Collectively, these findings enhance our understanding of cytoprotective signaling associated with photostress-induced NO and suggest iNOS inhibitor-based approaches for improving PDT efficacy.

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  • The cause for this phenomenon was shown due to the activation of PI3K and NF-κB pathways, inhibition of which dampened the NO production and its negative biological consequences.

    “Although how PDT-induced NO promotes tumor cell survival and invasiveness remains an open question, the cause for this phenomenon was shown due to the activation of PI3K and NF-κB pathways, inhibition of which dampened the NO production and its negative biological consequences [143,147,148].”

    From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [143]

    The Results sections on PI3K inhibition and NF-κB report that blocking these pathways prevented photostress-induced iNOS upregulation and increased apoptosis, supporting their role in NO-associated survival. The paper does not establish that these pathways explain NO-driven invasiveness; the Discussion also says how NO acts cytoprotectively remains to be determined. Page numbers are unavailable in our copy. (LLM, conf=0.85)

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Authors
Bhowmick, R., & Girotti, A. W.
Affiliations
Medical College of Wisconsin (US)
Corresponding author
  • Bhowmick, Reshma
  • Girotti, Albert W.
ORCID
Girotti, Albert W.
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2013-04
Volume
57
Pages
39-48
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2012.12.005
PMC
PMC3594367
OpenAlex
W2043778347
Cited by
67
References
59
Citations by year
2026: 1 · 2025: 2 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 2 · 2020: 5 · 2019: 8 · 2018: 3 · 2017: 2 · 2016: 8 · 2015: 15 · 2014: 5 · 2013: 5
FWCI
6.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
USPHS (CA70823)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
Keywords
photodynamic therapy, nitric oxide, inducible nitric oxide synthase, 5-aminolevulinic acid, apoptosis resistance, NF-κB nuclear translocation, JNK, p38 MAPK, Akt, p53, survivin, breast cancer, oxidative stress, 1400W, MDA-MB-231 cells
MeSH terms
Survivin, Adenocarcinoma, Aminolevulinic Acid, Breast Neoplasms, Enzyme Inhibitors, Female, Humans, Nitric Oxide, Nitriles, Photochemotherapy, Sulfones, NF-kappa B, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Cytoprotection, MAP Kinase Signaling System, Protein Transport, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Apoptosis Regulatory Proteins, Inhibitor of Apoptosis Proteins, Proto-Oncogene Proteins c-akt, Nitric Oxide Synthase Type II

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