PLA2R1 mediates tumor suppression by activating JAK2

David Vindrieux, Arnaud Augert, Christophe A. Girard, Delphine Gitenay, Helene Lallet-Daher, Clotilde Wiel, Benjamin Le Calve, Baptiste Gras, Mylene Ferrand, Stephanie Verbeke, Yvan De Launoit, Xavier Leroy, Alain Puisieux, Sébastien Aubert, Michael Perrais, Michael Gelb, Helene Simonnet, Gerard Lambeau, David Bernard

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

Little is known about the physiological role of the phospholipase A2 receptor (PLA2R1). PLA2R1 has been described as regulating the replicative senescence, a telomerase-dependent proliferation arrest. The downstream PLA2R1 signaling and its role in cancer are currently unknown. Senescence induction in response to activated oncogenes is a failsafe program of tumor suppression that must be bypassed for tumorigenesis. We now present evidence that PLA2R1 functions in vitro as a tumor suppressor, the depletion of which is sufficient to escape oncogene-induced senescence (OIS), thereby facilitating oncogenic cell transformation. Furthermore, mice that are genetically deficient in PLA2R1 display increased sensitivity to RAS-induced tumorigenesis by facilitating OIS escape, highlighting its physiological role as a tumor suppressor. Unexpectedly, PLA2R1 activated JAK2 and its effector signaling, with PLA2R1-mediated inhibition of cell transformation largely reverted in JAK2-depleted cells. This finding was unexpected as the JAK2 pathway has been associated mainly with protumoral functions and several inhibitors are currently in clinical trials. Taken together, our findings uncover an unanticipated tumor suppressive role for PLA2R1 that is mediated by targeting downstream JAK2 effector signaling.

langue originaleAnglais
Pages (de - à)6334-6345
Nombre de pages12
journalCancer Research
Volume73
Numéro de publication20
Les DOIs
étatPublié - 15 oct. 2013
Modification externeOui

Empreinte digitale

Oncogenes
Neoplasms
Phospholipase A2 Receptors
Carcinogenesis
Cell Aging
Telomerase
Clinical Trials

Citer ceci

Vindrieux, D., Augert, A., Girard, C. A., Gitenay, D., Lallet-Daher, H., Wiel, C., ... Bernard, D. (2013). PLA2R1 mediates tumor suppression by activating JAK2. Cancer Research, 73(20), 6334-6345. https://doi.org/10.1158/0008-5472.CAN-13-0318
Vindrieux, David ; Augert, Arnaud ; Girard, Christophe A. ; Gitenay, Delphine ; Lallet-Daher, Helene ; Wiel, Clotilde ; Le Calve, Benjamin ; Gras, Baptiste ; Ferrand, Mylene ; Verbeke, Stephanie ; De Launoit, Yvan ; Leroy, Xavier ; Puisieux, Alain ; Aubert, Sébastien ; Perrais, Michael ; Gelb, Michael ; Simonnet, Helene ; Lambeau, Gerard ; Bernard, David. / PLA2R1 mediates tumor suppression by activating JAK2. Dans: Cancer Research. 2013 ; Vol 73, Numéro 20. p. 6334-6345.
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title = "PLA2R1 mediates tumor suppression by activating JAK2",
abstract = "Little is known about the physiological role of the phospholipase A2 receptor (PLA2R1). PLA2R1 has been described as regulating the replicative senescence, a telomerase-dependent proliferation arrest. The downstream PLA2R1 signaling and its role in cancer are currently unknown. Senescence induction in response to activated oncogenes is a failsafe program of tumor suppression that must be bypassed for tumorigenesis. We now present evidence that PLA2R1 functions in vitro as a tumor suppressor, the depletion of which is sufficient to escape oncogene-induced senescence (OIS), thereby facilitating oncogenic cell transformation. Furthermore, mice that are genetically deficient in PLA2R1 display increased sensitivity to RAS-induced tumorigenesis by facilitating OIS escape, highlighting its physiological role as a tumor suppressor. Unexpectedly, PLA2R1 activated JAK2 and its effector signaling, with PLA2R1-mediated inhibition of cell transformation largely reverted in JAK2-depleted cells. This finding was unexpected as the JAK2 pathway has been associated mainly with protumoral functions and several inhibitors are currently in clinical trials. Taken together, our findings uncover an unanticipated tumor suppressive role for PLA2R1 that is mediated by targeting downstream JAK2 effector signaling.",
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Vindrieux, D, Augert, A, Girard, CA, Gitenay, D, Lallet-Daher, H, Wiel, C, Le Calve, B, Gras, B, Ferrand, M, Verbeke, S, De Launoit, Y, Leroy, X, Puisieux, A, Aubert, S, Perrais, M, Gelb, M, Simonnet, H, Lambeau, G & Bernard, D 2013, 'PLA2R1 mediates tumor suppression by activating JAK2', Cancer Research, VOL. 73, Numéro 20, p. 6334-6345. https://doi.org/10.1158/0008-5472.CAN-13-0318

PLA2R1 mediates tumor suppression by activating JAK2. / Vindrieux, David; Augert, Arnaud; Girard, Christophe A.; Gitenay, Delphine; Lallet-Daher, Helene; Wiel, Clotilde; Le Calve, Benjamin; Gras, Baptiste; Ferrand, Mylene; Verbeke, Stephanie; De Launoit, Yvan; Leroy, Xavier; Puisieux, Alain; Aubert, Sébastien; Perrais, Michael; Gelb, Michael; Simonnet, Helene; Lambeau, Gerard; Bernard, David.

Dans: Cancer Research, Vol 73, Numéro 20, 15.10.2013, p. 6334-6345.

Résultats de recherche: Contribution à un journal/une revueArticle

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T1 - PLA2R1 mediates tumor suppression by activating JAK2

AU - Vindrieux, David

AU - Augert, Arnaud

AU - Girard, Christophe A.

AU - Gitenay, Delphine

AU - Lallet-Daher, Helene

AU - Wiel, Clotilde

AU - Le Calve, Benjamin

AU - Gras, Baptiste

AU - Ferrand, Mylene

AU - Verbeke, Stephanie

AU - De Launoit, Yvan

AU - Leroy, Xavier

AU - Puisieux, Alain

AU - Aubert, Sébastien

AU - Perrais, Michael

AU - Gelb, Michael

AU - Simonnet, Helene

AU - Lambeau, Gerard

AU - Bernard, David

PY - 2013/10/15

Y1 - 2013/10/15

N2 - Little is known about the physiological role of the phospholipase A2 receptor (PLA2R1). PLA2R1 has been described as regulating the replicative senescence, a telomerase-dependent proliferation arrest. The downstream PLA2R1 signaling and its role in cancer are currently unknown. Senescence induction in response to activated oncogenes is a failsafe program of tumor suppression that must be bypassed for tumorigenesis. We now present evidence that PLA2R1 functions in vitro as a tumor suppressor, the depletion of which is sufficient to escape oncogene-induced senescence (OIS), thereby facilitating oncogenic cell transformation. Furthermore, mice that are genetically deficient in PLA2R1 display increased sensitivity to RAS-induced tumorigenesis by facilitating OIS escape, highlighting its physiological role as a tumor suppressor. Unexpectedly, PLA2R1 activated JAK2 and its effector signaling, with PLA2R1-mediated inhibition of cell transformation largely reverted in JAK2-depleted cells. This finding was unexpected as the JAK2 pathway has been associated mainly with protumoral functions and several inhibitors are currently in clinical trials. Taken together, our findings uncover an unanticipated tumor suppressive role for PLA2R1 that is mediated by targeting downstream JAK2 effector signaling.

AB - Little is known about the physiological role of the phospholipase A2 receptor (PLA2R1). PLA2R1 has been described as regulating the replicative senescence, a telomerase-dependent proliferation arrest. The downstream PLA2R1 signaling and its role in cancer are currently unknown. Senescence induction in response to activated oncogenes is a failsafe program of tumor suppression that must be bypassed for tumorigenesis. We now present evidence that PLA2R1 functions in vitro as a tumor suppressor, the depletion of which is sufficient to escape oncogene-induced senescence (OIS), thereby facilitating oncogenic cell transformation. Furthermore, mice that are genetically deficient in PLA2R1 display increased sensitivity to RAS-induced tumorigenesis by facilitating OIS escape, highlighting its physiological role as a tumor suppressor. Unexpectedly, PLA2R1 activated JAK2 and its effector signaling, with PLA2R1-mediated inhibition of cell transformation largely reverted in JAK2-depleted cells. This finding was unexpected as the JAK2 pathway has been associated mainly with protumoral functions and several inhibitors are currently in clinical trials. Taken together, our findings uncover an unanticipated tumor suppressive role for PLA2R1 that is mediated by targeting downstream JAK2 effector signaling.

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U2 - 10.1158/0008-5472.CAN-13-0318

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Vindrieux D, Augert A, Girard CA, Gitenay D, Lallet-Daher H, Wiel C et al. PLA2R1 mediates tumor suppression by activating JAK2. Cancer Research. 2013 oct. 15;73(20):6334-6345. https://doi.org/10.1158/0008-5472.CAN-13-0318