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

• Published in: Oncotarget Vol. 5; no. 13; pp. 5100 - 5112
• Main Authors: Okada, Masashi, Shibuya, Keita, Sato, Atsushi, Seino, Shizuka, Suzuki, Shuhei, Seino, Manabu, Kitanaka, Chifumi
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 15.07.2014
• Subjects: 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); ras Proteins - genetics; ras Proteins - metabolism; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction - drug effects; Signal Transduction - genetics; Tumor Burden - drug effects; Tumor Burden - genetics; Xenograft Model Antitumor Assays - methods
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.2087

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.