Receptor tyrosine kinase-like orphan receptor 1, a target of NKX2-1/TTF-1 lineage-survival oncogene, inhibits apoptosis signal-regulating kinase 1-mediated pro-apoptotic signaling in lung adenocarcinoma.

Abstract

We previously identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a transcriptional target of the NKX2-1/TTF-1 lineage-survival oncogene in lung adenocarcinoma. ROR1 consequently sustains a favorable balance between pro-survival phosphatidylinositol 3-kinase-protein kinase B and pro-apoptotic apoptosis signal-regulating kinase 1 (ASK1)-p38MAPK signaling. In contrast to recent advances in understanding how ROR1 sustains pro-survival signaling, the mechanism of ROR1 repression of pro-apoptotic signaling remains rather elusive. In the present study, we investigated the underlying mechanism of ROR1-mediated inhibition of the ASK1-p38MAPK signaling pathway. Growth inhibition mediated by siROR1 was partially but significantly alleviated by ASK1 co-knockdown in lung adenocarcinoma cell lines. Also, ASK1 phosphorylation at Thr845, which reflects its activated state, was clearly inhibited by ROR1 overexpression in both steady state and oxidative stress-elicited conditions in MSTO-211H cells. In addition, we found that ROR1 was physically associated with ASK1 at the C-terminal serine threonine-rich domain of ROR1. Furthermore, ROR1 kinase activity was shown to be required to repress the ASK1-p38 axis and oxidative stress-induced cell death. The present findings thus support our notion that ROR1 sustains lung adenocarcinoma survival, at least in part, through direct physical interaction with ASK1 and consequential repression of the pro-apoptotic ASK1-p38 axis in a ROR1 kinase activity-dependent manner.

• Authors: Lisa Ida, Tomoya Yamaguchi, Kiyoshi Yanagisawa, Taisuke Kajino, Yukako Shimada, Motoshi Suzuki, Takashi Takahashi
• Journal: Cancer science (Cancer Sci) Vol. 107 Issue 2 Pg. 155-61 (Feb 2016) ISSN: 1349-7006 [Electronic] England
• PMID: 26661061 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• DNA-Binding Proteins
• NKX2-1 protein, human
• Nuclear Proteins
• RNA, Small Interfering
• TTF1 protein, human
• Thyroid Nuclear Factor 1
• Transcription Factors
• ROR1 protein, human
• Receptor Tyrosine Kinase-like Orphan Receptors
• MAP Kinase Kinase Kinase 5
• MAP3K5 protein, human

Topics

• Adenocarcinoma (metabolism)
• Apoptosis (physiology)
• Blotting, Western
• Cell Line, Tumor
• DNA-Binding Proteins (metabolism)
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (physiology)
• Humans
• Immunoprecipitation
• Lung Neoplasms (metabolism)
• MAP Kinase Kinase Kinase 5 (metabolism)
• Nuclear Proteins (metabolism)
• Oncogenes
• RNA, Small Interfering
• Receptor Tyrosine Kinase-like Orphan Receptors (metabolism)
• Signal Transduction (physiology)
• Thyroid Nuclear Factor 1
• Transcription Factors (metabolism)
• Transfection