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Chemotherapeutic agents augment TRAIL-induced apoptosis in human hepatocellular carcinoma cell lines
T Yamanaka1, K Shiraki, K Sugimoto
1First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan.
Abstract:
TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in various transformed cell lines but not in almost-normal tissues. It is regulated by 2 death receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2, and 2 decoy receptors, TRAIL-R3 and TRAIL-R4. We investigated the expression of TRAIL-R- and TRAIL-induced apoptosis in human hepatocellular carcinomas (HCCs). TRAIL-R1, -R2, and -R4 were expressed in 6 HCC cell lines examined, but TRAIL-R3 was expressed in only 2 of the 6 cell lines. In addition, immunohistochemical results revealed a high and prevalent expression of TRAIL-R1 and -R2 in human HCC tissues. Despite the expression of TRAIL-R1 and -R2, all 6 HCC cell lines showed resistance to TRAIL-induced apoptosis with no relation to nuclear factor kappa B (NF-kappaB) levels induced by TRAIL. TRAIL-induced death signal was inhibited with both decreased caspase-8 and caspase-3 activity. However, TRAIL induced significant apoptosis in the presence of a subtoxic level of actinomycin D, indicating that the TRAIL-induced apoptotic pathway is in place in these cell lines. In addition, we found that treatment with conventional chemotherapeutic agents, doxorubicin and camptothecin, dramatically augmented TRAIL-induced cytotoxicity in most of the HCC cell lines. Actinomycin D and camptothecin almost completely suppressed NF-kappaB induction by TRAIL, whereas doxorubicin had little effect. These results indicate that TRAIL, in combination with chemotherapeutic agents, may have therapeutic potential in the treatment of human HCC.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows potential for treating hepatocellular carcinoma (HCC). TRAIL combined with chemotherapy agents overcomes TRAIL resistance in HCC cells, suggesting a promising therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Apoptosis Signaling
Background:
- TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells via TRAIL-R1 and TRAIL-R2.
- Hepatocellular carcinoma (HCC) often exhibits resistance to apoptosis-inducing agents.
Purpose of the Study:
- To investigate TRAIL receptor expression and TRAIL-induced apoptosis in human HCC.
- To evaluate the efficacy of combining TRAIL with chemotherapeutic agents against HCC.
Main Methods:
- Assessed TRAIL receptor expression (TRAIL-R1, -R2, -R3, -R4) in HCC cell lines and tissues using immunohistochemistry.
- Evaluated TRAIL-induced apoptosis and its modulation by chemotherapeutic agents (doxorubicin, camptothecin, actinomycin D).
- Measured caspase activity and nuclear factor kappa B (NF-kappaB) induction.
Main Results:
- TRAIL-R1, -R2, and -R4 were expressed in HCC cell lines; TRAIL-R1 and -R2 were highly expressed in HCC tissues.
- HCC cell lines were resistant to TRAIL-induced apoptosis, despite expressing death receptors.
- Combination therapy with TRAIL and chemotherapeutic agents (actinomycin D, camptothecin) significantly enhanced HCC cell apoptosis.
Conclusions:
- TRAIL resistance in HCC is not linked to NF-kappaB levels but involves inhibited caspase activity.
- TRAIL-induced apoptosis pathways are functional in HCC cells.
- Combining TRAIL with conventional chemotherapeutic agents presents a potential therapeutic strategy for human HCC.