摘要
Tumor hypoxia drives metastatic progression, drug resistance, and posttreatment relapses, but how cancer cells adapt and evolve in response to hypoxic stress is not well understood. In this study, we address this question with the discovery that the receptor tyrosine kinase RON translocates into the nucleus of hypoxic cancer cells. In response to hypoxia, nuclear RON interacts with the hypoxia-inducible factor HIF-1α in a manner that relies on RON tyrosine kinase activity, binding to the c-JUN promoter and activating it. Mechanistic investigations revealed unexpectedly that nuclear RON played a more important role in activation of the c-JUN promoter than HIF-1α, leading to increased cell proliferation, survival adaptation, in vitro migration, and tumorigenicity under hypoxic conditions. Taken together, our results pointed to a novel function for RON as a transcriptional regulator that promotes the survival of cancer cells subjected to hypoxia. These results suggest novel implications for the use of small-molecule inhibitors or monoclonal antibodies targeting the RON kinase in the prevention or treatment of advanced cancer.
| 原文 | English |
|---|---|
| 頁（從 - 到） | 4549-4562 |
| 頁數 | 14 |
| 期刊 | Cancer Research |
| 卷 | 74 |
| 發行號 | 16 |
| DOIs | |
| 出版狀態 | Published - 2014 八月 15 |
指紋
All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
引用此文
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Hypoxia promotes nuclear translocation and transcriptional function in the oncogenic tyrosine kinase RON. / Chang, Hong Yi; Liu, Hsiao Sheng; Lai, Ming Derg; Tsai, Yuh Shyan; Tzai, Tzong Shin; Cheng, Hong Ling; Chow, Nan Haw.
於: Cancer Research, 卷 74, 編號 16, 15.08.2014, p. 4549-4562.研究成果: Article
TY - JOUR
T1 - Hypoxia promotes nuclear translocation and transcriptional function in the oncogenic tyrosine kinase RON
AU - Chang, Hong Yi
AU - Liu, Hsiao Sheng
AU - Lai, Ming Derg
AU - Tsai, Yuh Shyan
AU - Tzai, Tzong Shin
AU - Cheng, Hong Ling
AU - Chow, Nan Haw
PY - 2014/8/15
Y1 - 2014/8/15
N2 - Tumor hypoxia drives metastatic progression, drug resistance, and posttreatment relapses, but how cancer cells adapt and evolve in response to hypoxic stress is not well understood. In this study, we address this question with the discovery that the receptor tyrosine kinase RON translocates into the nucleus of hypoxic cancer cells. In response to hypoxia, nuclear RON interacts with the hypoxia-inducible factor HIF-1α in a manner that relies on RON tyrosine kinase activity, binding to the c-JUN promoter and activating it. Mechanistic investigations revealed unexpectedly that nuclear RON played a more important role in activation of the c-JUN promoter than HIF-1α, leading to increased cell proliferation, survival adaptation, in vitro migration, and tumorigenicity under hypoxic conditions. Taken together, our results pointed to a novel function for RON as a transcriptional regulator that promotes the survival of cancer cells subjected to hypoxia. These results suggest novel implications for the use of small-molecule inhibitors or monoclonal antibodies targeting the RON kinase in the prevention or treatment of advanced cancer.
AB - Tumor hypoxia drives metastatic progression, drug resistance, and posttreatment relapses, but how cancer cells adapt and evolve in response to hypoxic stress is not well understood. In this study, we address this question with the discovery that the receptor tyrosine kinase RON translocates into the nucleus of hypoxic cancer cells. In response to hypoxia, nuclear RON interacts with the hypoxia-inducible factor HIF-1α in a manner that relies on RON tyrosine kinase activity, binding to the c-JUN promoter and activating it. Mechanistic investigations revealed unexpectedly that nuclear RON played a more important role in activation of the c-JUN promoter than HIF-1α, leading to increased cell proliferation, survival adaptation, in vitro migration, and tumorigenicity under hypoxic conditions. Taken together, our results pointed to a novel function for RON as a transcriptional regulator that promotes the survival of cancer cells subjected to hypoxia. These results suggest novel implications for the use of small-molecule inhibitors or monoclonal antibodies targeting the RON kinase in the prevention or treatment of advanced cancer.
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UR - http://www.scopus.com/inward/citedby.url?scp=84905964443&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-13-3730
DO - 10.1158/0008-5472.CAN-13-3730
M3 - Article
C2 - 24903148
AN - SCOPUS:84905964443
VL - 74
SP - 4549
EP - 4562
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 16
ER -