CHAP31 induces apoptosis only via the intrinsic pathway in human esophageal cancer cells.
OBJECTIVE
The antitumor mechanism of histone deacetylase (HDAC) inhibitors differs from conventional antitumor agents. HDAC inhibitors may be effective as novel therapeutic agents for esophageal squamous cell carcinoma (ESCC). This study describes the antiproliferative activity of CHAP31, a novel HDAC inhibitor. Furthermore, the molecular mechanism of CHAP31-induced apoptosis was investigated in ESCC.


RESULTS
The antitumor activity of CHAP31 was tested in esophageal cancer cell lines (T.Tn and TE2), and potent antitumor activity was observed in vitro and in vivo. In addition, CHAP31 induced apoptosis in esophageal cancer cells. Next, the mechanisms of CHAP31-induced apoptosis were examined using quantitative real-time RT-PCR and Western blotting. No processing of caspase 8 was observed, but CHAP31 induced the cleavage of caspase 9 and up-regulation of the Bax/Bcl-2 protein ratio.


CONCLUSIONS
This study provides new and important information on the potent antitumor activity of CHAP31 and the apoptotic pathway induced by CHAP31 in human esophageal cancer cell lines T.Tn and TE2. In contrast to previous reports showing that apoptosis induced by HDAC inhibitors includes the extrinsic pathway, in our study, apoptosis induced by CHAP31 in the human esophageal cell lines T.Tn and TE2 involved only the intrinsic pathway.
Murakami
Kentaro
K
Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. matsuhm @ faculty.chiba-u.jp
Matsubara
Hisahiro
H
Hoshino
Isamu
I
Akutsu
Yasunori
Y
Miyazawa
Yukimasa
Y
Matsushita
Kazuyuki
K
Sakata
Haruhito
H
Nishimori
Takanori
T
Usui
Akihiro
A
Kano
Masayuki
M
Nishino
Norikazu
N
Yoshida
Minoru
M
D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004938:Esophageal Neoplasms; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D010456:Peptides, Cyclic / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C505396:cyclic hydroxamic acid-containing peptide 31