Targeting the K-Ras - JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation
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Masashi Okada1, Keita Shibuya1,2,3, Atsushi Sato1,4, Shizuka Seino1,2,3,5, Shuhei Suzuki1,6, Manabu Seino1,7 and Chifumi Kitanaka1,2,3,5
1 Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan
2 Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata, Japan
3 Global COE program for Medical Sciences, Japan Society for Promotion of Science, Tokyo, Japan
4 Department of Neurosurgery, Yamagata University School of Medicine, Yamagata, Japan
5 Research Institute for Promotion of Medical Sciences, Yamagata University School of Medicine, Yamagata, Japan
6 Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata, Japan
7 Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata, Japan
Chifumi Kitanaka, email:
Keywords: pancreatic ductal adenocarcinoma (PDAC), xenograft analysis, tumorigenicity, cancer initiating cell
Received: March 21, 2014 Accepted: June 10, 2014 Published: June 10, 2014
Cancer cells with self-renewal and tumor-initiating capacity, either quiescent (cancer stem cells, CSCs) or proliferating (cancer stem-like cells, CSLCs), are now deemed responsible for the pervasive therapy resistance of pancreatic cancer, one of the deadliest human cancers characterized by high prevalence of K-Ras mutation. However, to date, much remains unknown how pancreatic CSCs/CSLCs are regulated. Here we show that the K-Ras – JNK axis plays a pivotal role in the maintenance of pancreatic CSCs/CSLCs. In vitro inhibition of JNK, either pharmacological or genetic, caused loss of the self-renewal and tumor-initiating capacity of pancreatic CSLCs. Importantly, JNK inhibition in vivo via systemic JNK inhibitor administration, which had no discernible effect on the general health status of mice, efficiently depleted the CSC/CSLC population within pre-established pancreatic tumor xenografts. Furthermore, knockdown of K-Ras in pancreatic CSLCs with K-Ras mutation led to downregulation of the JNK pathway as well as in loss of self-renewal and tumor-initiating capacity. Together, our findings suggest that pancreatic CSCs/CSLCs are dependent on K-Ras activation of JNK and also suggest that the K-Ras – JNK axis could be a potential target in CSC/CSLC-directed therapies against pancreatic cancer.
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