Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/TNFSF10/Apo2L) holds promise for cancer therapy as it induces apoptosis in a large variety of cancer cells while exerting negligible toxicity in normal ones. However, TRAIL can also induce proliferative and migratory signaling in cancer cells resistant to apoptosis induced by this cytokine. In that regard, the molecular mechanisms underlying the tumor selectivity of TRAIL and those balancing apoptosis versus survival remain largely elusive. We show here that high mRNA levels of PLAU, which encodes urokinase plasminogen activator (uPA), are characteristic of cancer cells with functional TRAIL signaling. Notably, decreasing uPA levels sensitized cancer cells to TRAIL, leading to markedly increased apoptosis. Mechanistic analyses revealed three molecular events taking place in uPA-depleted cells: reduced basal ERK1/2 prosurvival signaling, decreased preligand decoy receptor 2 (DcR2)-death receptor 5 (DR5) interaction and attenuated recruitment of DcR2 to the death-inducing signaling complex upon TRAIL challenge. These phenomena were accompanied by increased FADD and procaspase-8 recruitment and processing, thus guiding cells toward a caspase-dependent cell death that is largely independent of the intrinsic apoptosis pathway. Collectively, our results unveil PLAU mRNA levels as marker for the identification of TRAIL-responsive tumor cells and highlight a key role of uPA signaling in 'apoptosis versus survival' decision-making processes upon TRAIL challenge.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UdS/CERBM, BP10142, 67404 Illkirch Graffenstaden, France.
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Pavet
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UdS/CERBM, BP10142, 67404 Illkirch Graffenstaden, France.
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Shlyakhtina
Medical Biotechnology, VTT Technical Research Centre of Finland and University of Turku, Turku, Finland.
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He
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UdS/CERBM, BP10142, 67404 Illkirch Graffenstaden, France.
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Ceschin
Medical Biotechnology, VTT Technical Research Centre of Finland and University of Turku, Turku, Finland.
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Kohonen
Medical Biotechnology, VTT Technical Research Centre of Finland and University of Turku, Turku, Finland.
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Perälä
FIMM-Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
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Kallioniemi
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UdS/CERBM, BP10142, 67404 Illkirch Graffenstaden, France.
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Gronemeyer
D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D011485:Protein Binding; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D014568:Urokinase-Type Plasminogen Activator; D053181:Caspase 8