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RhoC GTPase Activation Assay

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Published on: August 22, 2010

The glucocorticoid receptor associates with RAS complexes to inhibit cell proliferation and tumor growth

Bozhena Caratti¹, Miray Fidan¹, Giorgio Caratti¹

¹Institute of Comparative Molecular Endocrinology, University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany.

Science Signaling

|March 22, 2022

Abstract:

Mutations that activate members of the RAS family of GTPases are associated with various cancers and drive tumor growth. The glucocorticoid receptor (GR), a member of the nuclear receptor family, has been proposed to interact with and inhibit the activation of components of the PI3K-AKT and MAPK pathways downstream of RAS. In the absence of activating ligands, we found that GR was present in cytoplasmic KRAS-containing complexes and inhibited the activation of wild-type and oncogenic KRAS in mouse embryonic fibroblasts and human lung cancer A549 cells. The DNA binding domain of GR was involved in the interaction with KRAS, but GR-dependent inhibition of RAS activation did not depend on the nuclear translocation of GR. The addition of ligand released GR-dependent inhibition of RAS, AKT, the MAPK p38, and the MAPKK MEK. CRISPR-Cas9-mediated deletion of GR in A549 cells enhanced tumor growth in xenografts in mice. Patient samples of non-small cell lung carcinomas showed lower expression of NR3C1, the gene encoding GR, compared to adjacent normal tissues and lower NR3C1 expression correlated with a worse disease outcome. These results suggest that glucocorticoids prevent the ability of GR to limit tumor growth by inhibiting RAS activation, which has potential implications for the use of glucocorticoids in patients with cancer.

Insights

Glucocorticoid receptor (GR) inhibits RAS activation, a key driver of cancer growth. Loss of GR function in lung cancer patients correlates with worse outcomes, suggesting therapeutic potential.

Area of Science:

Molecular Biology
Oncology
Endocrinology

Background:

RAS GTPases mutations drive tumor growth and are common in cancer.
Glucocorticoid receptor (GR) may inhibit RAS-mediated signaling pathways like PI3K-AKT and MAPK.

Purpose of the Study:

To investigate the interaction between GR and KRAS.
To determine the role of GR in regulating RAS activation and tumor growth.
To explore the clinical relevance of GR in non-small cell lung carcinoma (NSCLC).

Main Methods:

Cell culture experiments using mouse embryonic fibroblasts and human lung cancer A549 cells.
CRISPR-Cas9 gene editing to delete GR.
Xenograft tumor growth studies in mice.
Analysis of patient NSCLC samples for NR3C1 expression.

Main Results:

GR directly interacts with KRAS in the cytoplasm, inhibiting wild-type and oncogenic KRAS activation.
GR-mediated inhibition of RAS is ligand-independent and does not require nuclear translocation.
Ligand binding releases GR-mediated inhibition of RAS, AKT, p38 MAPK, and MEK MAPKK.
GR deletion in A549 cells enhances tumor growth in vivo.
Lower NR3C1 (GR gene) expression in NSCLC tissues correlates with poorer patient outcomes.

Conclusions:

GR acts as a negative regulator of RAS activation, impacting tumor growth.
Reduced GR expression in NSCLC is linked to adverse disease outcomes.
Glucocorticoids may influence cancer progression by modulating GR's inhibitory effect on RAS.

Read full analysis

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