# Molecular mechanisms of cNOS-mediated NF-kappa B activation in regulation of ultraviolet B light-induced photocarcinogenic responses

> **NIH NIH R01** · OHIO UNIVERSITY ATHENS · 2021 · $339,750

## Abstract

Abstract
Ultraviolet B radiation (UVB) is an environmental carcinogen, which is one of the major causative factors of
skin cancer formation. Activation of NF-kB has been shown to play an important role in carcinogenesis by
inhibiting apoptosis and therefore enhancing cell transformation. Thus, the NF-kB signaling network has been
a major target for development of therapeutics for prevention of UVB-induced skin carcinogenesis. We
reported a non-canonical pathway for activation of NF-kB that is mediated by constitutive nitric oxide synthase
(cNOS) in the early phase (6 h) after UVB irradiation. At the same time, activation of cNOS is expected to
promote cell damage by producing toxic peroxynitrite (ONOO−) from nitric oxide (NO•) and superoxide (O2−•).
Therefore, UVB-induced activation of cNOS promotes skin carcinogenesis by increasing the extent of DNA
damage, decreasing the capacity of DNA damage repair and promoting the survival of damaged cells. This
finding suggests that cNOS inhibitors could protect against development of skin cancer via blocking the
synergistic effect of DNA damage and anti-apoptotic activity of NF-kB. A desirable property of cNOS as a
target is that it only affects UVB-induced but not TNFa-induced NF-kB activation. The objective of this
proposal is to elucidate the fundamental molecular mechanism of UVB-induced skin carcinogenic responses
through a detailed study of cNOS-coordinated pro-death oxidative/nitrosative stress and DNA damage as well
as pro-survival NF-kB activation and autophagy induction. The innovation of this proposal resides on the
novel hypotheses that UVB-induced early phase NF-kB activation is solely dependent on cNOS activation;
and cNOS is a promising potential target for chemoprevention of UVB-induced skin carcinogenesis. This
hypothesis is based on the oncogenic properties of cNOS in causing DNA damage, activating NF-kB, and
inducing autophagy via NF-kB-regulated stabilization of IKKa. In addition, the proposed mechanism for
regulation and the functional role of NF-kB-IKKa signaling cascade is a novel conceptual ‘reversal’ of the
normal IKKa-NF-kB signaling. The therapeutic use of cNOS inhibitors in preventing UVB-induced DNA
damage, cell death, as well as skin carcinogenesis is clinically innovative. The proposed study can potentially
lead to the development of new therapeutics for chemoprevention and treatment of UVB-induced skin cancer.

## Key facts

- **NIH application ID:** 10146385
- **Project number:** 5R01ES030425-03
- **Recipient organization:** OHIO UNIVERSITY ATHENS
- **Principal Investigator:** Shiyong Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $339,750
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146385

## Citation

> US National Institutes of Health, RePORTER application 10146385, Molecular mechanisms of cNOS-mediated NF-kappa B activation in regulation of ultraviolet B light-induced photocarcinogenic responses (5R01ES030425-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10146385. Licensed CC0.

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