PAK1 tyrosine phosphorylation is required to induce epithelial-mesenchymal transition and radioresistance in lung cancer cells.

Abstract

The p21-activated Ser/Thr kinase 1 (PAK1) kinase has an essential role in tumorigenesis and cell survival in many cancers, but its regulation is not fully understood. In this study, we showed that in response to irradiation of lung cancer cells, PAK1 was upregulated, tyrosine phosphorylated, and translocated to the nucleus. Tyrosine phosphorylation relied upon JAK2 kinase activity and was essential for PAK1 protein stability and binding to Snail. This radiation-induced JAK2-PAK1-Snail signaling pathway increased epithelial-mesenchymal transition (EMT) by regulating epithelial and mesenchymal cell markers. Notably, JAK2 inhibitors mediated radiosensitization and EMT blockade in a mouse xenograft model of lung cancer. Taken together, our findings offered evidence that JAK2 phosphorylates and stabilizes functions of PAK1 that promote EMT and radioresistance in lung cancer cells, with additional implications for the use of JAK2 inhibitors as radiosensitizers in lung cancer treatment.

• Authors: EunGi Kim, HyeSook Youn, TaeWoo Kwon, Beomseok Son, JiHoon Kang, Hee Jung Yang, Ki Moon Seong, Wanyeon Kim, BuHyun Youn
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 19 Pg. 5520-31 (Oct 01 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 25125660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Tyrosine
• PAK1 protein, human
• p21-Activated Kinases

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (enzymology, pathology, radiotherapy)
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition
• Humans
• Lung Neoplasms (enzymology, pathology, radiotherapy)
• Mice
• Phosphorylation
• Radiation Tolerance
• Tyrosine (metabolism)
• p21-Activated Kinases (chemistry, metabolism)