Heat shock proteins play a crucial role in tumor-specific apoptosis by REIC/Dkk-3.
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.
Abarzua
Fernando
F
Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Sakaguchi
Masakiyo
M
Tanimoto
Ryuta
R
Sonegawa
Hiroyuki
H
Li
Dai-Wei
DW
Edamura
Kohei
K
Kobayashi
Tomoko
T
Watanabe
Masami
M
Kashiwakura
Yuji
Y
Kaku
Haruki
H
Saika
Takashi
T
Nakamura
Keiichiro
K
Nasu
Yasutomo
Y
Kumon
Hiromi
H
Huh
Nam-Ho
NH
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*
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