TWEAK signals through JAK-STAT to induce tumor cell apoptosis
Mark S Chapman1, Lan Wu, Aldo Amatucci
1Molecular Discovery, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
Cytokine
|October 31, 2012
Summary
The TWEAK/Fn14 pathway signals through JAK-STAT to induce apoptosis in tumor cells, even without interferon gamma. This mechanism, involving interferon beta production, is key for developing Fn14 agonists as cancer therapeutics.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- The TWEAK receptor Fn14 is a target for cancer therapeutics due to its role in apoptosis.
- Interferon gamma (IFNγ) typically enhances TWEAK/Fn14-induced apoptosis in tumor cells.
- The precise signaling mechanisms underlying TWEAK/Fn14 activity and IFNγ potentiation remain under investigation.
Purpose of the Study:
- To elucidate the role of JAK-STAT signaling in TWEAK/Fn14-mediated tumor cell killing.
- To investigate the interplay between IFNγ signaling and TWEAK/Fn14 pathway activation.
- To explore the potential of Fn14 agonists as cancer therapeutics.
Main Methods:
- Utilized cell culture experiments with tumor cell lines.
- Employed JAK inhibitors to assess the dependency on JAK-STAT signaling.
- Administered Fn14 agonistic antibody (mBIIB036) to tumor-bearing mice.
- Analyzed STAT1 phosphorylation in tumors and cell surface receptor expression.
Main Results:
- IFNγ-enhanced tumor cell killing is JAK-STAT dependent.
- IFNγ increases Fn14 expression on tumor cells, potentially sensitizing them to TWEAK.
- TWEAK alone induces STAT1 phosphorylation and apoptosis in WiDr cells via JAK-STAT signaling.
- TWEAK induces IFNβ production, which can independently activate STAT1.
- In vivo, mBIIB036 treatment phosphorylates STAT1 in tumors, correlating with tumor growth inhibition.
Conclusions:
- TWEAK/Fn14 signaling activates the JAK-STAT pathway, leading to tumor cell apoptosis and IFNβ production.
- The JAK-STAT pathway is central to TWEAK/Fn14-mediated tumor cell killing, both with and without IFNγ.
- IFNγ enhances TWEAK/Fn14 efficacy through JAK-dependent mechanisms, possibly involving increased Fn14 expression.
- These findings support the clinical development of Fn14 agonists for cancer therapy.
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