title: Heat shock proteins play a crucial role in tumor-specific apoptosis by REIC/Dkk-3.
abstract: We recently showed that overexpression of REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in a tumor cell-specific manner. The aim of the present study was to determine the mechanisms underlying the selective induction of apoptosis. At first, we found a mouse renal carcinoma cell line, RENCA, to be extremely sensitive to an adenovirus carrying REIC/Dkk-3 (Ad-REIC), and we showed that activation of c-Jun N-terminal kinase (JNK) was a critical step in cell death, i.e. a process similar to that in human prostate and testicular cancer observed in our previous studies. Among the proteins interfering with the activation of JNK, heat shock protein (Hsp)70/72 was reduced in expression in RENCA cells compared with that in NIH3T3 cells. An Hsp70/72 inducer protected RENCA cells from Ad-REIC-induced apoptosis, while an Hsp70/72 inhibitor sensitized NIH3T3 cells for apoptosis induction. These results indicate that functionally active Hsp70/72 is a key factor in tumor cell-specific induction of apoptotic cell death and that analyses of the expression levels of Hsp70/72 may be essential in determining the significance of Ad-REIC-based gene therapy against human cancer.
authors.affiliation: Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Fernando
authors.initials: F
authors.lastname: Abarzua
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
authors.forename: Ryuta
authors.initials: R
authors.lastname: Tanimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sonegawa
authors.forename: Dai-Wei
authors.initials: DW
authors.lastname: Li
authors.forename: Kohei
authors.initials: K
authors.lastname: Edamura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Masami
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kashiwakura
authors.forename: Haruki
authors.initials: H
authors.lastname: Kaku
authors.forename: Takashi
authors.initials: T
authors.lastname: Saika
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Nasu
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kumon
authors.forename: Nam-Ho
authors.initials: NH
authors.lastname: Huh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007680:Kidney Neoplasms / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C405061:Dkk3 protein, mouse; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins; D048031:JNK Mitogen-Activated Protein Kinases