Identification of serum and glucocorticoid-regulated kinase 1 as a regulator of signal transducer and activator of transcription 3 signaling.

Abstract

Signal transducer and activator of transcription 3 (STAT3) plays key roles in cancer cell proliferation, invasion, and immunosuppression. In many human cancer cells, STAT3 is hyperactivated, which leads to tumor progression and drug resistance, and therefore STAT3 and its modulators are considered effective drug targets. However, the complex regulatory mechanisms of STAT3 have made it difficult to develop potent anticancer drugs that suppress its activity. Here, we report serum and glucocorticoid-regulated kinase 1 (SGK1) as a novel regulator of STAT3 signaling and an effective target for combination therapy with Janus kinase (JAK) inhibitors. We screened small molecules using a gain-of-function mutant of STAT3 resistant to JAK inhibition and found that an SGK1 inhibitor suppressed the constitutive activation of STAT3. Importantly, our results revealed that SGK1 also mediated the activation of wild-type STAT3. Further examination suggested that the tuberous sclerosis complex 2 and mammalian target of rapamycin signaling pathway were involved in STAT3 activation by SGK1. Finally, we demonstrated that SGK1 inhibition enhanced the inhibitory effect of a JAK inhibitor on STAT3 phosphorylation and cancer cell proliferation. Our findings provide new insights into the molecular mechanisms of STAT3 activation and suggest SGK1 as a potential target for STAT3-targeted combination cancer therapy.

• Authors: Toshihiro Araki, Yuuki Watanabe, Yusuke Okada, Hisashi Murakami, Naohisa Ogo, Akira Asai
• Journal: Experimental cell research (Exp Cell Res) Vol. 413 Issue 2 Pg. 113079 (04 15 2022) ISSN: 1090-2422 [Electronic] United States
• PMID: 35202674 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Immediate-Early Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Protein Serine-Threonine Kinases
• serum-glucocorticoid regulated kinase

Topics

• Cell Line, Tumor
• Humans
• Immediate-Early Proteins (genetics)
• Neoplasms
• Phosphorylation
• Protein Serine-Threonine Kinases (genetics)
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction