Targeting the K-Ras--JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation

Masashi Okada; Keita Shibuya; Atsushi Sato; Shizuka Seino; Shuhei Suzuki; Manabu Seino; Chifumi Kitanaka

doi:10.18632/oncotarget.2087

Targeting the K-Ras--JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation

Oncotarget. 2014 Jul 15;5(13):5100-12. doi: 10.18632/oncotarget.2087.

Authors

Masashi Okada¹, Keita Shibuya, Atsushi Sato, Shizuka Seino, Shuhei Suzuki, Manabu Seino, Chifumi Kitanaka²

Affiliations

¹ Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.
² Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan; Oncology Research Center, Research Institute for Advanced Molecular Epidemiology, Yamagata University, Yamagata, Japan; Global COE program for Medical Sciences, Japan Society for Promotion of Science, Tokyo, Japan; Research Institute for Promotion of Medical Sciences, Yamagata University School of Medicine, Yamagata, Japan.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AC133 Antigen
Animals
Anthracenes / pharmacology
Antigens, CD / genetics
Antigens, CD / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Gene Expression Regulation, Neoplastic
Glycoproteins / genetics
Glycoproteins / metabolism
Humans
Immunoblotting
Male
Mice, Inbred BALB C
Mice, Nude
Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 8 / genetics*
Mitogen-Activated Protein Kinase 8 / metabolism
Mitogen-Activated Protein Kinase 9 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 9 / genetics*
Mitogen-Activated Protein Kinase 9 / metabolism
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / pathology
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / prevention & control
Peptides / genetics
Peptides / metabolism
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins p21(ras)
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects
Signal Transduction / genetics
Tumor Burden / drug effects
Tumor Burden / genetics
Xenograft Model Antitumor Assays / methods
ras Proteins / genetics*
ras Proteins / metabolism

Substances

AC133 Antigen
Anthracenes
Antigens, CD
Glycoproteins
KRAS protein, human
Peptides
Proto-Oncogene Proteins
pyrazolanthrone
Mitogen-Activated Protein Kinase 9
Mitogen-Activated Protein Kinase 8
Proto-Oncogene Proteins p21(ras)
ras Proteins