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Updated: Mar 18, 2026

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Loss of inducible nitric oxide synthase promotes Kras/Pten-driven lung tumorigenesis

Zahra Kabiri1,2,3, Hamed Zaribafzadeh1,2, Sara Raji2

  • 1Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, United States.

Frontiers in Cell and Developmental Biology
|March 16, 2026
PubMed

Insights

Loss of inducible nitric oxide synthase (iNOS) normally reduces lung tumors. However, in mice lacking the Pten tumor suppressor, iNOS loss unexpectedly worsened lung cancer outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Inducible nitric oxide synthase (iNOS) plays complex roles in cancer, acting as both a promoter and suppressor.
  • In Kras-driven lung adenocarcinoma models, iNOS deficiency typically reduces tumor growth.

Purpose of the Study:

  • To investigate the impact of iNOS loss on lung tumorigenesis when the tumor suppressor Pten is also lost.
  • To determine if the anti-tumorigenic effect of iNOS deficiency is maintained in the presence of Pten loss.

Main Methods:

  • Utilized oncogenic Kras-driven mouse models of lung adenocarcinoma.
  • Compared lung tumorigenesis in mice with combined Kras activation and Pten inactivation, with and without iNOS.
  • Monitored tumor development, lesion characteristics, survival, tumor burden, and macrophage infiltration.

Main Results:

  • Loss of iNOS did not alter the number or type of lung lesions in Pten-deficient mice.
  • iNOS deficiency was associated with significantly shortened survival.
  • Reduced iNOS led to increased tumor burden and intratumoral macrophage infiltration in the Pten-deficient context.

Conclusions:

  • The previously observed anti-neoplastic effect of iNOS deficiency is reversed in Kras-driven lung cancer when Pten is lost.
  • Genetic context, specifically the presence or absence of Pten, critically influences the role of iNOS in lung tumorigenesis.
  • These findings highlight the context-dependent nature of iNOS function in cancer development.
Keywords:
NSCLCPTENRASiNOSmacrophagenitric oxidenitric oxide synthasenon-small cell lung cancer

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