Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells

V. Pavet (Corresponding Author), Y. Shlyakhtina, Tao He, D.G. Geschin, P. Kohonen, M. Perälä, O. Kallioniemi, H. Gronemeyer (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

10 Citations (Scopus)

Abstract

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
Original languageEnglish
Article numbere1043
JournalCell Death and Disease
Volume5
DOIs
Publication statusPublished - 2014
MoE publication typeA1 Journal article-refereed

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Plasminogen Activators
Urokinase-Type Plasminogen Activator
Cell Survival
Apoptosis
Neoplasms
Death Domain Receptor Signaling Adaptor Proteins
TNF-Related Apoptosis-Inducing Ligand Receptors
Messenger RNA
Caspase 8
Caspases
Decision Making
Cell Death
Tumor Necrosis Factor-alpha
Cytokines
Ligands

Cite this

Pavet, V., Shlyakhtina, Y., He, T., Geschin, D. G., Kohonen, P., Perälä, M., ... Gronemeyer, H. (2014). Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells. Cell Death and Disease, 5, [e1043]. https://doi.org/10.1038/cddis.2014.5
Pavet, V. ; Shlyakhtina, Y. ; He, Tao ; Geschin, D.G. ; Kohonen, P. ; Perälä, M. ; Kallioniemi, O. ; Gronemeyer, H. / Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells. In: Cell Death and Disease. 2014 ; Vol. 5.
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abstract = "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",
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Pavet, V, Shlyakhtina, Y, He, T, Geschin, DG, Kohonen, P, Perälä, M, Kallioniemi, O & Gronemeyer, H 2014, 'Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells', Cell Death and Disease, vol. 5, e1043. https://doi.org/10.1038/cddis.2014.5

Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells. / Pavet, V. (Corresponding Author); Shlyakhtina, Y.; He, Tao; Geschin, D.G.; Kohonen, P.; Perälä, M.; Kallioniemi, O.; Gronemeyer, H. (Corresponding Author).

In: Cell Death and Disease, Vol. 5, e1043, 2014.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells

AU - Pavet, V.

AU - Shlyakhtina, Y.

AU - He, Tao

AU - Geschin, D.G.

AU - Kohonen, P.

AU - Perälä, M.

AU - Kallioniemi, O.

AU - Gronemeyer, H.

PY - 2014

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AB - 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

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DO - 10.1038/cddis.2014.5

M3 - Article

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JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

M1 - e1043

ER -