EMT induced RIP1 expression defines TRAIL sensitivity in carcinoma cells

Abstract

Despite recent advances in biomarker discovery and therapeutic options, metastasis still stands as the primary reason for cancer-related mortality. This highlights the pressing need for the identification of new targets for the treatment of metastases, and new markers of metastatic capability, to tailor aggressive therapy to higher-risk cases. Metastatic cells often become therapy-resistant, and this necessitates novel therapeutic interventions. Epithelial-Mesenchymal Transition (EMT) is the key cellular process inducing metastatic phenotype in cancers.
Cell culture, western blotting, flow cytometry and microscopy techniques were used in this study. We used naturally epithelial or mesenchymal carcinoma cell lines, TGF−induced EMT model and a stable ZEB1 knock-down (Mesenchymal-Epithelial Transition) MET model.
TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand) is known to induce apoptosis in a subset of cancer cells. We hypothesized EMT status of cancer correlates with TRAIL sensitivity. We initially classified a total of 11 (breast and colorectal cancer) cell lines in terms of their EMT status and TRAIL response. Mesenchymal cells responded to TRAIL better than their epithelial counterparts. Proteins that were shown to influence TRAIL response were examined towards their contribution to TRAIL sensitivity and classified according to the EMT status of cell lines. RIP1 expression pattern matched TRAIL sensitive/mesenchymal phenotype. RIP1 holds a critical position in cellular pathways leading to enhanced survival (via NF-κB activation), apoptosis (via death receptor ligation) and necroptosis (via inhibited caspase-8 activity). Our results suggest that RIP1 is actively utilized by the naturally chemo-resistant metastatic cancer cells to gain survival advantage but can be used to direct cellular response from enhanced survival to cell death with TRAIL stimulation.
This study provided evidence that RIP1 is involved in the sensitivity of mesenchymal cells to TRAIL.
Overall, an increased understanding of the survival/apoptosis pathways of metastatic cells will help us devise new potential prognostic biomarkers and therapeutic regimens for cancer therapy.

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Identifiers

ORCID for Emre Sayan: orcid.org/0000-0002-5291-1485

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