title: Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6.
abstract: Ninety percent of human pancreatic cancer is characterized by activating K-RAS mutations. TRAF6 is an oncogene that plays a vital role in K-RAS-mediated oncogenesis. We investigated the synergistic effect of combining ionizing radiation (IR) and proteasome inhibitor (MG132). Furthermore, following combined treatment with IR and MG132, we analyzed the expression of TRAF6 and the mechanism of human pancreatic cancer cell death in vitro and in an orthotopic pancreatic cancer mouse model. The combined treatment groups displayed synergistic cell killing effects and induced endoplasmic reticulum stress in human pancreatic cancer cells. The combined treatment groups were characterized by enhanced cytotoxicity, which resulted from increased autophagy induction through the inhibition of TRAF6. Significantly reduced cytotoxicity was observed following MG132 and IR treatment of MIA PaCa-2 cells pre-treated with 3-MA (an autophagy inhibitor). Down-regulation of TRAF6 led to a significant increase in apoptosis and autophagy. In an orthotopic xenograft model of SCID mice, combination MG132 and IR therapy resulted in a significant increase in the tumor growth delay time and a decreased tumor tissue expression of TRAF6. IR combined with a proteasome inhibitor or TRAF6 inhibition could represent a new therapeutic strategy for human pancreatic cancer.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Chiu
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Lin
authors.affiliation: Department of Radiation Oncology, Chi Mei Medical Center, Tainan, Taiwan; School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Lin
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yung-Ho
authors.initials: YH
authors.lastname: Hsu
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yuh-Feng
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Department of Radiation Oncology, Chi Mei Medical Center, Liouying, Tainan, Taiwan; Chang Jung Christian University, Tainan, Taiwan.
authors.forename: Sheng-Yow
authors.initials: SY
authors.lastname: Ho
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan; Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: wuyh@mail.ncku.edu.tw.
authors.forename: Yuan-Hua
authors.initials: YH
authors.lastname: Wu
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan; Department of Biomedical Informatics, Asia University, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. Electronic address: yjwang@mail.ncku.edu.tw.
authors.forename: Ying-Jan
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000235:genetics; D003131:Combined Modality Therapy; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007976:Leupeptins / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D034622:RNA Interference; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6 / Q000096:biosynthesis / Q000235:genetics*; D014183:Transplantation, Heterologous
chemical_list: D007976:Leupeptins; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D048029:TNF Receptor-Associated Factor 6; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Autophagy; Endoplasmic reticulum stress; Pancreatic cancer; Proteasome inhibitor; Radiation