Down-regulation of cIAP2 enhances 5-FU sensitivity through the apoptotic pathway in human colon cancer cells.
Currently 5-fluorouracil (5-FU) plays a central role in the chemotherapeutic regimens for colorectal cancers and thus it is important to understand the mechanisms that determine 5-FU sensitivity. The expression profiles of human colon cancer cell line DLD-1, its 5-FU-resistant subclone DLD-1/FU and a further 21 types of colon cancer cell lines were compared to identify the novel genes defining the sensitivity to 5-FU and to estimate which population of genes is responsible for 5-FU sensitivity. In the hierarchical clustering, DLD-1 and DLD-1/FU were most closely clustered despite over 100 times difference in their 50% inhibitory concentration of 5-FU. In DLD-1/FU, the population of genes differentially expressed compared to DLD-1 was limited to 3.3%, although it ranged from 4.8% to 24.0% in the other 21 cell lines, thus indicating that the difference of 5-FU sensitivity was defined by a limited number of genes. Next, the role of the cellular inhibitor of apoptosis 2 (cIAP2) gene, which was up-regulated in DLD-1/FU, was investigated for 5-FU resistance using RNA interference. The down-regulation of cIAP2 efficiently enhanced 5-FU sensitivity, the activation of caspase 3/7 and apoptosis under exposure to 5-FU. The immunohistochemistry of cIAP2 in cancer and corresponding normal tissues from colorectal cancer patients in stage III revealed that cIAP2 was more frequently expressed in cancer tissues than in normal tissues, and cIAP2-positive patients had a trend toward early recurrence after fluorouracil-based chemotherapy. Although the association between drug sensitivity and the IAP family in colorectal cancer has not yet been discussed, cIAP2 may therefore play an important role as a target therapy in colorectal cancer.
Karasawa
Hideaki
H
Division of Biological-Regulation and Oncology, Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan 980-8574.
Miura
Koh
K
Fujibuchi
Wataru
W
Ishida
Kazuyuki
K
Kaneko
Naoyuki
N
Kinouchi
Makoto
M
Okabe
Mitsunori
M
Ando
Toshinori
T
Murata
Yukio
Y
Sasaki
Hiroyuki
H
Takami
Kazuhiro
K
Yamamura
Akihiro
A
Shibata
Chikashi
C
Sasaki
Iwao
I
D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases
D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D053148:Caspase 3; D053179:Caspase 7; D005472:Fluorouracil