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Trail induces cell migration and invasion in apoptosis-resistant cholangiocarcinoma cells
Norihisa Ishimura1, Hajime Isomoto, Steven F Bronk
1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA.
Abstract:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for cancer therapy; however, many cholangiocarcinoma cells are resistant to TRAIL-mediated apoptosis. Resistance to apoptosis may unmask TRAIL signaling cascades favoring tumor biology. Thus our aim was to examine whether TRAIL is expressed by human cholangiocarcinomas, and if so, to determine whether it promotes a malignant phenotype. To address this objective, TRAIL expression in human liver specimens was evaluated by immunohistochemistry. The effect of TRAIL on tumor cell migration, invasion, and proliferation was examined in three human cholangiocarcinoma cell lines. TRAIL expression was upregulated by cholangiocytes in preneoplastic disease, primary sclerosing cholangitis, and human cholangiocarcinoma specimens. TRAIL promoted tumor cell migration and invasion but did not induce cell proliferation. TRAIL-mediated cell migration and invasion was NF-kappaB dependent. These data demonstrate that TRAIL promotes cell migration and invasion via a NF-kappaB-dependent pathway in human cholangiocarcinoma cell lines, an observation that has a potential negative implication for TRAIL in cancer therapy.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes cholangiocarcinoma cell migration and invasion, not proliferation. This TRAIL signaling is NF-kappaB dependent, potentially limiting its cancer therapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic.
- Cholangiocarcinoma cells often exhibit resistance to TRAIL-induced apoptosis.
- Apoptosis resistance can paradoxically enhance tumor progression through TRAIL signaling.
Purpose of the Study:
- To investigate TRAIL expression in human cholangiocarcinomas.
- To determine if TRAIL promotes a malignant phenotype in cholangiocarcinoma.
- To elucidate the signaling pathways involved in TRAIL's effects.
Main Methods:
- Immunohistochemistry was used to assess TRAIL expression in human liver specimens.
- Three human cholangiocarcinoma cell lines were utilized to study TRAIL's effects.
- Assays for cell migration, invasion, and proliferation were performed.
- NF-kappaB pathway activation was investigated.
Main Results:
- TRAIL expression was elevated in cholangiocytes from preneoplastic lesions, primary sclerosing cholangitis, and cholangiocarcinoma.
- TRAIL significantly enhanced cholangiocarcinoma cell migration and invasion.
- TRAIL did not stimulate cholangiocarcinoma cell proliferation.
- TRAIL-induced migration and invasion were dependent on the NF-kappaB pathway.
Conclusions:
- TRAIL is upregulated in cholangiocarcinoma and associated conditions.
- TRAIL promotes cholangiocarcinoma cell migration and invasion through an NF-kappaB-dependent mechanism.
- These findings suggest potential limitations for TRAIL-based cancer therapy in cholangiocarcinoma due to promotion of malignant behavior.
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