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Involvement of clusterin expression in the refractory response of pancreatic cancer cells to a MEK inhibitor |
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| Authors: | Kohei Amada Naoki Hijiya Sawa Ikarimoto Kazuyoshi Yanagihara Toshikatsu Hanada Shinya Hidano Shusaku Kurogi Yoshiyuki Tsukamoto Chisato Nakada Keisuke Kinoshita Yuka Hirashita Tomohisa Uchida Toshitaka Shin Kazuhiro Yada Teijiro Hirashita Takashi Kobayashi Kazunari Murakami Masafumi Inomata Kuniaki Shirao Masahiro Aoki Mutsuhiro Takekawa Masatsugu Moriyama |
| Affiliation: | 1. Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan Department of Medical Oncology and Hematology, Faculty of Medicine, Oita University, Oita, Japan;2. Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan;3. Department of Plastic Surgery, Kagoshima City Hospital, Kagoshima, Japan;4. Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo, Japan;5. Department of Cell Biology, Faculty of Medicine, Oita University, Oita, Japan;6. Department of Infectious Disease Control, Faculty of Medicine, Oita University, Oita, Japan Department of Immune Regulation, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan;7. Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan Department of Urology, Faculty of Medicine, Oita University, Oita, Japan;8. Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan;9. Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Japan Department of Forensic Medicine, Faculty of Medicine, Oita University, Oita, Japan;10. Department of Urology, Faculty of Medicine, Oita University, Oita, Japan;11. Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, Oita, Japan;12. Department of Infectious Disease Control, Faculty of Medicine, Oita University, Oita, Japan;13. Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan;14. Department of Medical Oncology and Hematology, Faculty of Medicine, Oita University, Oita, Japan;15. Division of Pathophysiology, Aichi Cancer Center, Aichi, Japan;16. Division of Cell Signaling and Molecular Medicine, Institute of Medical Sciences, University of Tokyo, Tokyo, Japan |
| Abstract: | Constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway is essential for tumorigenesis of pancreatic ductal adenocarcinoma (PDAC). To date, however, almost all clinical trials of inhibitor targeting this pathway have failed to improve the outcome of patients with PDAC. We found that implanted MIA Paca2, a human PDAC cell line sensitive to a MAPK inhibitor, PD0325901, became refractory within a week after treatment. By comparing the expression profiles of MIA Paca2 before and after acquisition of the refractoriness to PD0325901, we identified clusterin (CLU) as a candidate gene involved. CLU was shown to be induced immediately after treatment with PD0325901 or expressed primarily in more than half of PDAC cell lines, enhancing cell viability by escaping from apoptosis. A combination of PD0325901 and CLU downregulation was found to synergistically or additively reduce the proliferation of PDAC cells. In surgically resected PDAC tissues, overexpression of CLU in cancer cells was observed immunohistochemically in approximately half of the cases studied. Collectively, our findings highlight the mechanisms responsible for the rapid refractory response to MEK inhibitor in PDAC cells, suggesting a novel therapeutic strategy that could be applicable to patients with PDAC using inhibitor targeting the MAPK signaling pathway and CLU. |
| Keywords: | apoptosis Clusterin drug refractoriness MEK inhibitor pancreatic cancer |