ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Cancer Cell Biology
Loss of Inducible Nitric Oxide Synthase Promotes Kras/Pten-driven Lung Tumorigenesis
Zahra Kabiri
Hamed Zaribafzadeh
Sara Raji
John M Carney
Christopher M Counter
Duke University, Durham, United States
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Abstract
The inducible Nitric Oxide Synthase (iNOS) enzyme has been implicated in both pro-and anti-tumorigenic processes, depending on the cancer context. In oncogenic Kras-driven mouse models of lung adenocarcinoma, the loss of iNOS reduces tumorigenesis. To explore the additional loss of the tumor suppressor Pten in this setting, we compared lung tumorigenesis in mice induced by activation of oncogenic Kras in conjunction with inactivation of Pten in the absence and presence of iNOS. We report that the loss of iNOS did not affect the number or type of lung lesions compared to control iNOS wild-type mice, but was associated with shortened overall survival that was accompanired by increased tumor burden and intratumoral macrophage infiltration. These findings suggest that the antineoplastic effect of iNOS deficiency in Kras-driven lung tumorigenesis is reversed upon the loss of Pten. Thus, even within the identical cancer model, the loss of iNOS can have opposite effects depending on the genetic context.
Summary
Keywords
iNOS, Nitric Oxide, Nitric Oxide Synthase, Non-small cell lung cancer, Pten, Ras
Received
17 May 2025
Accepted
19 February 2026
Copyright
© 2026 Kabiri, Zaribafzadeh, Raji, Carney and Counter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zahra Kabiri
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