Abstract
Interferon (IFN) combined with 5-Fluorouracil (5-FU) treatment has recently been reported to show beneficial effects in patients with advanced hepatocellular carcinoma. IFNα is usually provided for this combination therapy. In this study, we investigated the molecular mechanisms of apoptosis induction in hepatoma cell lines with IFNα and 5-FU combination therapy from the view point of 5-FU's additive effect on interferon-related signaling pathways. Five hepatoma cell lines (Hep3B, Huh7, HLE, PLC/PRF/5, and HepG2) were tested for apoptosis inducibility by IFNα in the absence or presence of 5-FU. Hep3B was the most apoptosis sensitive to IFN plus 5-FU treatment. The JAK/STAT pathway transcriptional factor ISRE was activated more synergistically when 5-FU was added to IFNα treatments. Caspase-3, -9, and especially caspase-8 activity was higher with IFN α plus 5-FU than IFN or 5-FU alone. Inhibition of caspase-8, -9, c-Jun N-terminal kinase (JNK), phosphatidylinositide 3-kinase (PI3K), and p38 mitogen-activated protein kinase (p38 MAPK) revealed that caspase-8 inhibition was the most effective at decreasing the apoptotic effects of IFN and/or 5-FU. In JAK1 and ISGF3γ-silenced Hep3B cells, the apoptosis induction and caspase-8 activation levels by IFN, even in combination with 5-FU, were abrogated. In conclusion, caspase-8 is the most important factor that controls IFN and 5-FU-induced apoptosis in hepatoma cell lines.
| Original language | English |
|---|---|
| Pages (from-to) | 1253-1261 |
| Number of pages | 9 |
| Journal | International Journal of Oncology |
| Volume | 29 |
| Issue number | 5 |
| Publication status | Published - Nov 2006 |
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Keywords
- 5-Flourouracil
- Hepatoma
- Interferon
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Combination of 5-FU and IFNα enhances IFN signaling pathway and caspase-8 activity, resulting in marked apoptosis in hepatoma cell lines. / Koike, Kazuko; Takaki, Akinobu; Tatsukawa, Masashi; Suzuki, Mayumi; Shiraha, Hidenori; Iwasaki, Yoshiaki; Sakaguchi, Kohsaku; Shiratori, Yasushi.
In: International Journal of Oncology, Vol. 29, No. 5, 11.2006, p. 1253-1261.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Combination of 5-FU and IFNα enhances IFN signaling pathway and caspase-8 activity, resulting in marked apoptosis in hepatoma cell lines
AU - Koike, Kazuko
AU - Takaki, Akinobu
AU - Tatsukawa, Masashi
AU - Suzuki, Mayumi
AU - Shiraha, Hidenori
AU - Iwasaki, Yoshiaki
AU - Sakaguchi, Kohsaku
AU - Shiratori, Yasushi
PY - 2006/11
Y1 - 2006/11
N2 - Interferon (IFN) combined with 5-Fluorouracil (5-FU) treatment has recently been reported to show beneficial effects in patients with advanced hepatocellular carcinoma. IFNα is usually provided for this combination therapy. In this study, we investigated the molecular mechanisms of apoptosis induction in hepatoma cell lines with IFNα and 5-FU combination therapy from the view point of 5-FU's additive effect on interferon-related signaling pathways. Five hepatoma cell lines (Hep3B, Huh7, HLE, PLC/PRF/5, and HepG2) were tested for apoptosis inducibility by IFNα in the absence or presence of 5-FU. Hep3B was the most apoptosis sensitive to IFN plus 5-FU treatment. The JAK/STAT pathway transcriptional factor ISRE was activated more synergistically when 5-FU was added to IFNα treatments. Caspase-3, -9, and especially caspase-8 activity was higher with IFN α plus 5-FU than IFN or 5-FU alone. Inhibition of caspase-8, -9, c-Jun N-terminal kinase (JNK), phosphatidylinositide 3-kinase (PI3K), and p38 mitogen-activated protein kinase (p38 MAPK) revealed that caspase-8 inhibition was the most effective at decreasing the apoptotic effects of IFN and/or 5-FU. In JAK1 and ISGF3γ-silenced Hep3B cells, the apoptosis induction and caspase-8 activation levels by IFN, even in combination with 5-FU, were abrogated. In conclusion, caspase-8 is the most important factor that controls IFN and 5-FU-induced apoptosis in hepatoma cell lines.
AB - Interferon (IFN) combined with 5-Fluorouracil (5-FU) treatment has recently been reported to show beneficial effects in patients with advanced hepatocellular carcinoma. IFNα is usually provided for this combination therapy. In this study, we investigated the molecular mechanisms of apoptosis induction in hepatoma cell lines with IFNα and 5-FU combination therapy from the view point of 5-FU's additive effect on interferon-related signaling pathways. Five hepatoma cell lines (Hep3B, Huh7, HLE, PLC/PRF/5, and HepG2) were tested for apoptosis inducibility by IFNα in the absence or presence of 5-FU. Hep3B was the most apoptosis sensitive to IFN plus 5-FU treatment. The JAK/STAT pathway transcriptional factor ISRE was activated more synergistically when 5-FU was added to IFNα treatments. Caspase-3, -9, and especially caspase-8 activity was higher with IFN α plus 5-FU than IFN or 5-FU alone. Inhibition of caspase-8, -9, c-Jun N-terminal kinase (JNK), phosphatidylinositide 3-kinase (PI3K), and p38 mitogen-activated protein kinase (p38 MAPK) revealed that caspase-8 inhibition was the most effective at decreasing the apoptotic effects of IFN and/or 5-FU. In JAK1 and ISGF3γ-silenced Hep3B cells, the apoptosis induction and caspase-8 activation levels by IFN, even in combination with 5-FU, were abrogated. In conclusion, caspase-8 is the most important factor that controls IFN and 5-FU-induced apoptosis in hepatoma cell lines.
KW - 5-Flourouracil
KW - Hepatoma
KW - Interferon
UR - http://www.scopus.com/inward/record.url?scp=39049180565&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=39049180565&partnerID=8YFLogxK
M3 - Article
C2 - 17016659
AN - SCOPUS:39049180565
VL - 29
SP - 1253
EP - 1261
JO - International Journal of Oncology
JF - International Journal of Oncology
SN - 1019-6439
IS - 5
ER -