Nitric Oxide Inhibits NF-κB-mediated Survival Signaling: Possible Role in Overcoming TRAIL Resistance.

Abstract

BACKGROUND/AIM:

Chemoresistance is a major consequence of multicycle chemotherapy and can be attributed to constitutive activation of pro-survival signaling pathways. Nitric oxide is a ubiquitous signaling molecule which has been shown to inhibit several pathways involved with survival signaling in cancer cells. We have previously demonstrated the anti-tumor activity of a nitric oxide-donor, nitrosylcobalamin (NO-Cbl), mediated by increased expression of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and its receptors in human tumors. We also demonstrated that a functional Apo2L/TRAIL receptor is necessary for the induction of cell death by NO-Cbl and the Apo2L/TRAIL death receptor DR4 (TRAIL R1) is S-nitrosylated. The aim of the study was to examine the effects of nitric oxide (NO) on nuclear factor kappa B (NF-κB) and determine whether nitric oxide could sensitize drug-resistant melanomas to Apo2L/TRAIL via inhibition of NF-κB or inhibitor kappa B kinase (IKK).

MATERIALS AND METHODS:

Antiproliferative effects of NO-Cbl and Apo2L/TRAIL were assessed in malignant melanomas and non-tumorigenic melanocyte and fibroblast cell lines. Athymic nude mice bearing human melanoma A375 xenografts were treated with NO-Cbl and Apo2L/TRAIL. Apoptosis was measured by the TUNEL assay. The activation status of NF-κB was established by assaying luciferase reporter activity, the phosphorylation status of IκBα, and in vitro IKK activity.

RESULTS:

NO-Cbl sensitized Apo2L/TRAIL-resistant melanoma cell lines to growth inhibition by Apo2L/TRAIL, but had minimal effect on normal cell lines. NO-Cbl and Apo2L/TRAIL exerted synergistic anti-tumor activity against A375 xenografts. NO-Cbl suppressed Apo2L/TRAIL- and TNF-α-mediated activation of a transfected NF-κB-driven luciferase reporter. NO-Cbl inhibited IKK activation, characterized by decreased phosphorylation of IκBα.

CONCLUSION:

NO-Cbl treatment rendered Apo2L/TRAIL-resistant malignancies sensitive to the anti-tumor effects of Apo2L/TRAIL in vitro and in vivo. The use of nitric oxide to inhibit NF-κB and potentiate the effects of chemotherapeutic agents, such as Apo2L/TRAIL, represents a promising anti-cancer combination based on recent clinical investigations of anti-TRAIL antibodies for cancer treatment strategies.

• Authors: Joseph A Bauer, Joseph A Lupica, Joseph A Didonato, Daniel J Lindner
• Journal: Anticancer research (Anticancer Res) Vol. 40 Issue 12 Pg. 6751-6763 (Dec 2020) ISSN: 1791-7530 [Electronic] Greece
• PMID: 33288568 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• NF-kappa B
• Nitroso Compounds
• TNF-Related Apoptosis-Inducing Ligand
• nitrosylcobalamin
• NF-KappaB Inhibitor alpha
• Nitric Oxide
• Vitamin B 12

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Humans
• Male
• Mice, Nude
• NF-KappaB Inhibitor alpha (metabolism)
• NF-kappa B (metabolism)
• Nitric Oxide (pharmacology)
• Nitroso Compounds (pharmacology)
• Signal Transduction
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Vitamin B 12 (analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays