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Open AccessArticle

The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation

by Ji-Hyang Kim 1,†, Hack Sun Choi 2,3,†, Su-Lim Kim 1,4 and Dong-Sun Lee 1,2,3,4,5,*
1
Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju 63243, Korea
2
Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, SARI, Jeju 63243, Korea
3
Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea
4
School of Biomaterials Science and Technology, College of Applied Life Science, Jeju National University, Jeju 63243, Korea
5
Practical Translational Research Center, Jeju National University, Jeju 63243, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(10), 1527; https://doi.org/10.3390/cancers11101527
Received: 12 August 2019 / Revised: 2 October 2019 / Accepted: 3 October 2019 / Published: 10 October 2019
(This article belongs to the Special Issue JAK-STAT Signalling Pathway in Cancer)
Cancer stem cells (CSCs) have unique properties, including self-renewal, differentiation, and chemoresistance. In this study, we found that p21-activated kinase (PAK1) inhibitor (Group I, PAK inhibitor, IPA-3) and inactivator (ivermectin) treatments inhibit cell proliferation and that tumor growth of PAK1-knockout cells in a mouse model is significantly reduced. IPA-3 and ivermectin inhibit CSC formation. PAK1 physically interacts with Janus Kinase 2 (JAK2), and JAK2 inhibitor (TG101209) treatment inhibits mammosphere formation and reduces the nuclear PAK1 protein level. PAK1 interacts with signal transducer and activator of transcription 3 (Stat3), and PAK1 and Stat3 colocalize in the nucleus. We show through electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and reporter assays that the PAK1/Stat3 complex binds to the IL-6 promoter and regulates the transcription of the IL-6 gene. Inhibition of PAK1 and JAK2 in mammospheres reduces the nuclear pStat3 and extracellular IL-6 levels. PAK1 inactivation inhibits CSC formation by decreasing pStat3 and extracellular IL-6 levels. Our results reveal that JAK2/PAK1 dysregulation inhibits the Stat3 signaling pathway and CSC formation, the PAK1/Stat3 complex regulates IL-6 gene expression, PAK1/Stat3 signaling regulates CSC formation, and PAK1 may be an important target for treating breast cancer. View Full-Text
Keywords: PAK1; cancer stem cell; Stat3; IL-6; mammosphere; JAK2 PAK1; cancer stem cell; Stat3; IL-6; mammosphere; JAK2
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Kim, J.-H.; Choi, H.S.; Kim, S.-L.; Lee, D.-S. The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation. Cancers 2019, 11, 1527.

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