Cadmium-induced malignant transformation of rat liver cells: Potential key role and regulatory mechanism of altered apolipoprotein E expression in enhanced invasiveness.
Cadmium is a transition metal that is classified as human carcinogen by the International Agency for Research on Cancer (IARC) with multiple target sites. Many studies using various model systems provide evidence of cadmium-induced malignancy formation in vivo or malignant cell transformation in vitro. Nonetheless, further studies are needed to completely understand the mechanisms of cadmium carcinogenicity. Our prior studies have utilized a rat liver epithelial cell line (TRL 1215) as a model for cadmium-induced malignant transformation. In the present study, we focused on the molecular mechanisms of this malignant transformation, especially with regard to hyper-invasiveness stimulated by cadmium transformation. By performing a series of biochemical analyses on cadmium transformed cells, it was determined that cadmium had significantly down-regulated the expression of apolipoprotein E (ApoE). ApoE was recently established as a suppressor of cell invasion. A key factor in the suppression of ApoE by cadmium appeared to be that the metal evoked a 5-aza-2'-deoxycytidine-sensitive hypermethylation of the regulatory region of ApoE, coupled with interference of the action of liver X receptor α (LXRα), a transcriptional regulator for ApoE. Furthermore, the expression of LXRα itself was suppressed by cadmium-mediated epigenetic modification. Re-expression of ApoE clearly abrogated the cell invasion stimulated by cadmium-induced malignant transformation. Together, the current results suggest that the cadmium-mediated enhanced cell invasion is linked to down-regulation of ApoE during malignant transformation these liver cells.
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Masayo
M
Suzuki
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Shuso
S
Takeda
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Noriko
N
Teraoka-Nishitani
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Akane
A
Yamagata
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Takahiro
T
Tanaka
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Marika
M
Sasaki
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Natsuki
N
Yasuda
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Makiko
M
Oda
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Tatsuji
T
Okano
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Kazuhiro
K
Yamahira
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.
Yuta
Y
Nakamura
Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, 1314-1, Shido, Sanuki, Kagawa 769-2193, Japan.
Takanobu
T
Kobayashi
Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, 1314-1, Shido, Sanuki, Kagawa 769-2193, Japan.
Katsuhito
K
Kino
Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, 1314-1, Shido, Sanuki, Kagawa 769-2193, Japan.
Hiroshi
H
Miyazawa
Raleigh, NC 27709, USA.
Michael P
MP
Waalkes
Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU), 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan. Electronic address: m-takigu@ps.hirokoku-u.ac.jp.
Masufumi
M
Takiguchi
D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002104:Cadmium / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D008099:Liver / Q000166:cytology; D000071518:Liver X Receptors / Q000819:agonists / Q000235:genetics; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics
D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D001565:Benzoates; D001596:Benzylamines; D002104:Cadmium; D002273:Carcinogens; D000071518:Liver X Receptors; D051780:Sterol Regulatory Element Binding Protein 1; C577834:Abca1 protein, rat; C473027:GW 3965; C497389:Srebf1 protein, rat
Apolipoprotein E; Cadmium; Cell invasion; DNA hypermethylation; Malignant transformation; TRL 1215 cells