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Regulation of the Src-PP2A interaction in tumor necrosis factor (TNF)-related apoptosis-inducing ligand
Jing Xu1, Zhengfan Xu, Jun-Ying Zhou
1From the Karmanos Cancer Institute, Departments of Oncology and Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201.
Abstract:
TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in transformed and tumor cells but not in normal cells, making it a promising agent for cancer therapy. However, many cancer cells are resistant to TRAIL, and the underlying mechanisms are not fully understood. Here, we show that the regulation of the PP2A and Src interaction plays a critical role in TRAIL resistance. Specifically, we show that TRAIL treatment activates the tyrosine kinase Src, which subsequently phosphorylates caspase-8 at tyrosine 380, leading to the inhibition of caspase-8 activation. We also show that upon TRAIL treatment, Src, caspase-8, and PP2A/C (a catalytic subunit of the PP2A phosphatase) are redistributed into lipid rafts, a microdomain of the plasma membrane enriched with cholesterol, where PP2A dephosphorylates Src at tyrosine 418 and in turn inhibits caspase-8 phosphorylation. Furthermore, we find that TRAIL treatment causes PP2A/C degradation. These data suggest that the balance between Src-mediated caspase-8 phosphorylation and the inactivation of Src-mediated caspase-8 phosphorylation by PP2A determines the outcome of TRAIL treatment in breast cancer cells. Therefore, this work identifies a novel mechanism by which the interaction between PP2A and Src in the context of caspase-8 activation modulates TRAIL sensitivity in cancer cells.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in cancer cells involves the interplay between PP2A and Src. This interaction regulates caspase-8 activation, influencing TRAIL
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Death Signaling
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for cancer therapy due to its selective induction of apoptosis in cancer cells.
- However, many cancer cells exhibit resistance to TRAIL, and the molecular mechanisms underlying this resistance are not fully elucidated.
- Understanding TRAIL resistance is crucial for developing effective cancer treatments.
Purpose of the Study:
- To investigate the role of the interaction between protein phosphatase 2A (PP2A) and Src in mediating resistance to TRAIL-induced apoptosis in cancer cells.
- To elucidate the specific molecular events involving Src, caspase-8, and PP2A during TRAIL treatment.
- To identify novel therapeutic targets for overcoming TRAIL resistance in cancer.
Main Methods:
- Analysis of Src activation and caspase-8 phosphorylation following TRAIL treatment in cancer cells.
- Investigation of the subcellular localization of Src, caspase-8, and PP2A/C in lipid rafts upon TRAIL stimulation.
- Assessment of PP2A/C levels and activity in response to TRAIL treatment.
Main Results:
- TRAIL treatment activates Src tyrosine kinase, leading to caspase-8 phosphorylation at Tyr380 and inhibition of its activation.
- TRAIL induces the redistribution of Src, caspase-8, and PP2A/C into lipid rafts, where PP2A dephosphorylates Src, thereby inhibiting caspase-8 phosphorylation.
- TRAIL treatment results in the degradation of PP2A/C, impacting the phosphatase's ability to regulate Src activity.
Conclusions:
- The balance between Src-mediated caspase-8 phosphorylation and PP2A-mediated inactivation of this phosphorylation dictates the sensitivity of breast cancer cells to TRAIL.
- A novel mechanism involving the dynamic interaction between PP2A and Src in regulating caspase-8 activation determines TRAIL sensitivity.
- Targeting the PP2A-Src interaction offers a potential strategy to enhance TRAIL efficacy in cancer therapy.
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