Related Experiment Video

Updated: Mar 8, 2026

Application of Genetically Encoded Fluorescent Nitric Oxide (NO•) Probes, the geNOps, for Real-time Imaging of NO• Signals in Single Cells

Application of Genetically Encoded Fluorescent Nitric Oxide (NO•) Probes, the geNOps, for Real-time Imaging of NO• Signals in Single Cells

Published on: March 16, 2017

Evaluating The Role Of Nitric Oxide Synthase In Oncogenic Ras-Driven Tumorigenesis

Chris Counter¹

¹Duke University Medical Center, Durham, USA.

|February 7, 2017

Abstract:

We previously reported that oncogenic KRAS activation of the PI3K/AKT pathway stimulates the remaining wild-type HRAS and NRAS proteins in a manner dependent upon both eNOS expression and C118 in HRAS and NRAS, which promoted tumor growth. Interestingly however, we recently found that loss of wild-type HRAS, NRAS, and even more potently, loss of both of these genes actually enhanced oncogenic KRAS-driven early tumorigenesis. Taken together, these results indicate that wild-type RAS proteins are tumor suppressing early in tumorigenesis, but tumor promoting in more malignant settings. Knock-in of a C118S mutation into an endogenous wild-type RAS gene did not, however, hamper oncogenic KRAS-driven tumor initiation. As such, redox-dependent reactions with C118 of wild-type RAS proteins are unlikely to be responsible for the tumor suppressive role of wild-type RAS proteins. This suggests that the redox-dependent reactions with C118 of wild-type RAS proteins are more important in more malignant settings. Given this, it stands to reason that inhibiting redox-dependent reactions like S-nitrosylation of wild-type RAS proteins may be more effective in established cancer settings. Indeed, we find that in three different models of KRAS-driven cancers-skin, pancreatic and lung- the general NOS inhibitor l-NAME reduced tumor burden and/or extended the lifespan of mice. Since oncogenic RAS has so far proven refractory to pharmacologic inhibition, targeting NOS activity may be an actionable approach to inhibiting RAS signaling for the treatment of a broad spectrum of cancers.

Insights

Wild-type RAS proteins suppress tumors early on but promote them later. Inhibiting nitric oxide synthase (NOS) activity effectively reduced KRAS-driven tumor growth in preclinical models.

Area of Science:

Oncology
Molecular Biology
Biochemistry

Background:

Oncogenic KRAS activates the PI3K/AKT pathway, stimulating wild-type HRAS and NRAS proteins, which promotes tumor growth.
Wild-type RAS proteins exhibit dual roles: tumor suppressive in early tumorigenesis and tumor promoting in advanced cancers.
Redox-dependent reactions involving C118 in wild-type RAS are implicated in later-stage tumor promotion.

Purpose of the Study:

To investigate the contrasting roles of wild-type RAS proteins in early versus advanced tumorigenesis.
To determine the role of C118 in wild-type RAS function during oncogenic KRAS-driven cancer.
To evaluate the therapeutic potential of inhibiting nitric oxide synthase (NOS) in KRAS-driven cancers.

Main Methods:

Analysis of oncogenic KRAS-driven tumorigenesis in the presence and absence of wild-type HRAS and NRAS.
Introduction of a C118S mutation into endogenous wild-type RAS genes.
Treatment with the general NOS inhibitor l-NAME in preclinical models of KRAS-driven skin, pancreatic, and lung cancers.

Main Results:

Loss of wild-type HRAS and NRAS enhanced early oncogenic KRAS-driven tumorigenesis.
A C118S mutation did not impede oncogenic KRAS-driven tumor initiation, suggesting C118's role is context-dependent.
Inhibition of NOS with l-NAME reduced tumor burden and/or improved survival in three distinct KRAS-driven cancer models.

Conclusions:

Wild-type RAS proteins function as tumor suppressors early in tumorigenesis but become tumor promoters in more malignant settings.
Redox-dependent reactions at C118 are crucial for the tumor-promoting function of wild-type RAS in established cancers.
Targeting NOS activity represents a promising therapeutic strategy for inhibiting oncogenic RAS signaling in various cancers.

Read full analysis

More Related Videos

Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo

Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo

Published on: July 20, 2019

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

Related Concept Videos

The Ras Gene

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...

Small GTPases - Ras and Rho

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:

Cancer-Critical Genes I: Proto-oncogenes

Cancer-Critical Genes I: Proto-oncogenes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...

mTOR Signaling and Cancer Progression

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...

Abnormal Proliferation

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...

Rous Sarcoma Virus (RSV) and Cancer

Rous Sarcoma Virus (RSV) and Cancer

Rous Sarcoma virus or RSV was discovered by F. Peyton Rous in the year 1911 as a filterable transmissible agent that could cause tumors in chickens. He won a Nobel Prize for this discovery in 1966. His experiments clearly demonstrated that some cancers could be caused by infectious agents and led to the discovery of many more cancer-causing viruses in animals as well as humans.
RSV is a retrovirus that contains two copies of a plus-strand RNA genome. Its genome consists of four main open...

Articles linked to this work by shared authors, journal, and citation graph.

CLPP loss confers sex-specific protection from renal ischemia reperfusion injury.

Redox biology·2026

Mitochondrial dysfunction and oxidative stress in OSAHS and associated comorbidities: Mechanism and potential targeted therapeutic strategies.

Redox biology·2026

Protein S-nitrosylation in the heart: Mechanisms, physiological roles, and pathological remodeling.

Redox biology·2026

Antiglycation approach in selected autoimmune diseases: Where do we stand?

Redox biology·2026

Dual promoter architecture of NFE2L2 underlies isoform-specific translational control of NRF2.

Redox biology·2026

Neutrophil extracellular traps delivering lactylated S100a9 aggravate neuronal cuproptosis by regulating Ttr/Commd1/Atp7b axis after traumatic brain injury.

Redox biology·2026

See all related articles