title: Targeting the K-Ras--JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation.
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.
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Okada
authors.forename: Keita
authors.initials: K
authors.lastname: Shibuya
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
authors.forename: Shizuka
authors.initials: S
authors.lastname: Seino
authors.forename: Shuhei
authors.initials: S
authors.lastname: Suzuki
authors.forename: Manabu
authors.initials: M
authors.lastname: Seino
authors.affiliation: 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.
authors.forename: Chifumi
authors.initials: C
authors.lastname: Kitanaka
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D000873:Anthracenes; D015703:Antigens, CD; D006023:Glycoproteins; C117307:KRAS protein, human; D010455:Peptides; D011518:Proto-Oncogene Proteins; C432165:pyrazolanthrone; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins