Caspase-2 regulates oncogene-induced senescence

International audienceCellular senescence is activated by numerous cellular insults, in particular those driving cancer formation, resulting in stable proliferation arrest and acquisition of specific features. By self-opposing to oncogenic stimulation, senescence is considered as a failsafe program, allowing, when functional, to inhibit cancers occurrence. Compelling evidences suggest a tumor suppressive activity of caspase-2, eventually independently of its effect on cell death. The original results described here demonstrate that this tumor suppressive activity of caspase-2 is mediated, at least in part, by its pro-senescing activity. Indeed, we have demonstrated in vitro and in vivo that loss of function of caspase-2 allows to escape oncogenic stress induced senescence. These results are discussed in the context of known tumor suppressive activity of caspase-2

Ganoderma lucidum : le champignon d’immortalité, nouvel allié dans la lutte contre la douleur induite lors de traitements anticancéreux

International audienceSi la phytothérapie a depuis longtemps acquis ses lettres de noblesse, le champignon demeure le parent pauvre dans le domaine dessoins naturels. Cependant, certaines espèces de champignons dont le ganoderme luisant (Ganoderma lucidum) sont utilisées depuis desmillénaires en Chine et au Japon comme aliments de longue vie et de jeunesse prolongée. Aujourd'hui, la mycothérapie est en pleinemutation, passant d'une médecine empirique à une science basée sur des preuves d’efficacité.Dans ce contexte, un nombre croissant d'études sont publiées chaque année afin de légitimer et de comprendre leurs utilisationstraditionnelles mais également de leur trouver de nouvelles propriétés pharmacologiques

Involvement of Ion Channels in Endothelin-1-induced Signalling in Human Prostate Cancer Cells

Objective: Endothelin-1 (ET-1), a potent vasoconstrictor secreted primarily by endothelial and various epithelial cancercells has been implicated in prostate cancer progression and the ET axis has been suggested to represent a novel andexciting target in the treatment of prostate cancer (PCa). ET-1, acting primarily through the endothelin receptors (ETRs)is integrally involved in multiple facets of PCa progression, including cell growth, inhibition of apoptosis, angiogenesis anddevelopment of bone metastases. ET-1 and ETRs are expressed in PCa tissues and their expression is modulated duringthe evolution of these cancers. The purpose of the present work was to study the effects of ET-1 on proliferation of humanPCa cells PC-3 and the mechanisms by which the activation of ETRs may promote the PCa cells growth.Methods: Prostate cancer cell lines and primary cultured epithelial cells from prostate cancer, RT-PCR and calciumimaging techniques were used to study the expression and functionality of the Endothelin receptors and involvement ofion channels in the effects of ET-1 in prostate cancer cells.Results: We show for the first time that the application of ET-1 induces a dose-dependent cell proliferation andan increase in intracellular free Ca2+ concentrations ([Ca2+]i) via a mobilisation of the internal calcium stores and bya capacitative calcium entry (CCE). These effects of ET-1 were completely abolished by BQ123, a selective ETARantagonist, but not by BQ788, a selective ETBR antagonist. By use of pharmacological inhibitors and siRNA targetingcalcium-activated (IKCa1 and BKCa) potassium channels and calcium channels (TRPC1, TRPV6, Orai1), we showedthat these ion channels play an important role in calcium entry and cell proliferation induced by ET-1 in PCa cells.Conclusion: These results suggest that these ions channels evidenced here might constitute potential targets toblock the ET axis in human prostate cancers

PLA2R1 Mediates Tumor Suppression by Activating JAK2

International audienceLittle 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