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Antitumor interaction at the cell membrane

Glucocorticoid receptor imposes a break on cancer progression

In non-small cell lung cancer and other tumor entities, RAS is a commonly mutated oncogene. This cancer gene feeds tumor growth and therapies failed to shut off mutated RAS. In an collaborative approach between Ulm University and the Center for Physiology and Pharmacology at the Medical University of Vienna, researchers now discovered a novel function of the glucocorticoid receptor: interacting with RAS proteins located at the cytoplasmic site of the cell membrane, this receptor blocks tumor growth. First results of this study were now published in “Science Signaling” and are highlighted at the cover of the journal.

Oncogenes trigger uncontrolled cell division and tumor growth. In almost one third of cancer diseases, mutated RAS plays a key role in tumor development and progression, including in cancers of the lung, pancreas and colon. Although RAS was discovered already in the early 80´s, targeted therapies are still not clinical routine due to various reasons. Regardless of the prime oncogenes, glucocorticoids are often used in cancer medicine, mainly to alleviate therapy related side effects. These glucocorticoids activate the glucocorticoid receptor (GR), which – upon activation – translocates into the nucleus to regulate gene expression. However, the impact of cytosolic expressed GR remained unclear. “RAS proteins are located at the cytoplasmic site of the cell membrane. Hence we hypothesized that extranuclear (i.e. cytosolic) GR interacts with RAS and blocks there activity.”, explained Ion Cirstea, researcher at Ulm University and one of the senior authors of this recent study.

To test this hypothesis, researchers of Ulm University and the Medical University Vienna designed a two-step project design. On one hand, the “gene scissors” CRISPR-Cas9 was used to knock out GR in KRAS mutant lung tumor cells, to analyze the activity of RAS independent of GR actions. How would this affect tumor growth? This question was addressed by different means, including flow cytometry, pull down assays, gene expression analysis and immunofluorescence. On the other hand, GR deficient lung tumor cells were subjected to in vivo experiments using mice, to evaluate whether these cells are still capable to establish tumors.

By this approach the international research team made serval intriguing discoveries. In the cytosol, both the GR and RAS proteins form a complex with other adaptor proteins, thereby downregulating activity of RAS oncogenes. However, as soon as GR gets stimulated and translocates into the nucleus, RAS activity is unleashed. Conversely, the glucocorticoid receptor is able to slow down RAS. “Based on our investigations we can confirm our hypothesis: we found indeed a cytosolic interaction of RAS proteins with GR, and apparently, this interaction can reduce the oncogenic potential of mutant RAS”, summarizes Bozhena Carratti, who completed her PhD thesis at Ulm University and was a visiting student at the Medical University of Vienna.

To the best of the knowledge of the research team, this was the first study addressing GR-RAS interactions in the context of tumorigenesis. “If it is possible to strengthen the interaction between RAS and GR, this may prevent the development of lung cancer”, explains Jan Tuckermann, Director of the Institute of Comparative Molecular Endocrinology at Ulm University. However, the interactions of GR with RAS and the larger protein complex would first need to be further characterized, which is currently addressed in a follow up study. This will be a pre-requisite to pave the way for clinical application.  
However, Herwig Moll (Medical University Of Vienna) points out the translational value of this study: “Big data analysis of gene expressions of lung cancer patients revealed that patients with decreased GR expression exhibited worse survival prognosis.”

The study was based on a strong collaboration between Ulm University and the Medical University of Vienna, and Herwig Moll (Vienna) and Ion Cirstea and Jan Tuckermann (Ulm) share the senior authorship of this study. The work was supported by the FWF, the DFG, the Fellinger Krebsforschung Fund, Funds of the German Cancer Aid and the German Network for RASopathy Research.

Service: Science Signaling
The glucocorticoid receptor associates with RAS complexes to inhibit cell proliferation and tumor growth.
Bozhena Caratti, Miray Fidan, Giorgio Caratti, Kristina Breitenecker, Melanie Engler, Naser Kazemitash, Rebecca Traut, Rainer Wittig, Emilio Casanova, Mohammad Reza Ahmadian, Jan P. Tuckermann, Herwig P. Moll, Ion Cristian Cirstea: Science Signaling DOI: 10.1126/scisignal.abm4452