Rôle de la voie PI3K-AKT-mTOR dans le cancer et les thérapeutiques antitumorales

Coutte, L.; Dreyer, Chantal; Sablin, Marie‐Paule; Faivre, Sandrine; Raymond, Éric

doi:10.1684/bdc.2011.1384

Cited by 32 publications

(18 citation statements)

References 32 publications

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“…One well-established pathway, the PI3K/Akt pathway, mediates pro-survival signals in various types of cancers [20]. In particular, Akt is involved in the inhibition of apoptosis via the phosphorylation of pro-apoptotic molecules, e.g., Bad or caspase-9, or the modulation of transcription factors, such as c-Raf [34]. At the molecular level, constitutive Akt activation (phosphor-Akt) was suppressed, and PARP cleavage and caspase-9 activity were increased in MCF7-shGPR81 cells, indicating an apoptotic signature.…”

Section: Discussionmentioning

confidence: 99%

G-protein-coupled receptor 81 promotes a malignant phenotype in breast cancer through angiogenic factor secretion

et al. 2016

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G-protein-coupled receptor 81 (GPR81) functions as a receptor for lactate and plays an important role in the regulation of anti-lipolytic effects in adipocytes. However, to data, a role for GPR81 in the tumor microenvironment has not been clearly defined. Here, GPR81 expression in breast cancer patients and several breast cancer cell lines was significantly increased compared with normal mammary tissues and cells. GPR81 knockdown resulted in impaired breast cancer growth and led to apoptosis both in vitro and in vivo. Furthermore, the inhibition of GPR81 signaling suppressed angiogenesis through a phosphoinositide 3-OH kinase (PI3K)/Akt-cAMP response element binding protein (CREB) pathway, which led to decreased production of the pro-angiogenic mediator amphiregulin (AREG). Overall, these findings identify GPR81 as a tumor-promoting receptor in breast cancer progression and suggest a novel mechanism that regulates GPR81-dependent activation of the PI3K/Akt signaling axis in tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

G-protein-coupled receptor 81 promotes a malignant phenotype in breast cancer through angiogenic factor secretion

et al. 2016

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“…c-Raf. [41]. Recent studies have shown that inhibition of PI3K/Akt might be a promising strategy to decrease the threshold for apoptosis induction via the death receptor triggering or cytotoxic drugs in neuroblastoma and glioblastoma [8,26,42].…”

Section: Discussionmentioning

confidence: 99%

Targeting PI3K/Akt represses Hypoxia inducible factor-1α activation and sensitizes Rhabdomyosarcoma and Ewing’s sarcoma cells for apoptosis

2013

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BackgroundHypoxia inducible factor-1 α (HIF-1α) has been identified as an important novel target in apoptosis resistance of pediatric tumors such as Rhabdomyosarcoma (RMS) and Ewing’s sarcoma (ES). Evidence suggests that PI3K/Akt signaling plays a role in regulation of HIF-1α activation as well as apoptosis resistance in various adult tumors. However the relevance of PI3K/Akt signaling in HIF-1bα activation and apoptosis resistance in childhood tumors has not been addressed yet. Thus, this study was to investigate whether PI3K/Akt signaling is involved in hypoxia induced activation of HIF-1α as well as in resistance to hypoxia-induced apoptosis in childhood tumors such as RMS and ES.MethodsConstitutive activation of PI3K/Akt signaling was analyzed by Western blotting. Hypoxic activation of HIF-1α was determined by Western Blot analysis and electrophoretic mobility shift assay. Apoptosis was determined by flow cytometric analysis of the propidium iodine stained nuclei of cells treated with PI3K inhibitor LY294002 in combination with either TNF-related apoptosis-inducing ligand (TRAIL) or doxorubicin.ResultsThis study demonstrated that PI3K/Akt signaling was constitutively activated in RMS and ES cell lines, A204 and A673, respectively. Targeting PI3K/Akt signaling by the inhibitor LY294002 (30 μM) significantly decreased the protein expression as well as DNA binding activity of HIF-1α and restored the apoptosis-inducing ability of cells in hypoxia Additionally, pretreatment with LY294002 sensitized A204 and A673 cells to TRAIL or doxorubicin induced apoptosis under hypoxia.ConclusionThese results suggest that the constitutively active PI3K/Akt signaling contributes to hypoxic activation of HIF-1α as well as HIF1α-mediated apoptosis resistance in RMS and ES cells under hypoxia.

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“…The phosphatidylinositol 3-kinase (PI3K), AKT serine/threonine kinase, mammalian target of rapamycin (PI3K/AKT/ mTOR) signaling pathway is aberrantly activated in many types of cancer. 1 For example, activating PIK3CA gene mutations affecting the PI3Kα catalytic subunit, such as H1047R, P449T, E545K and R88Q are detected in about~15-20% of colorectal cancers (CRC). 2,3 Therefore, components of the PI3K/mTOR pathway have been considered attractive drug targets.…”

Section: Introductionmentioning

confidence: 99%

Activation of WNT/β‐catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations

Park

Kim

Cho

et al. 2018

Intl Journal of Cancer

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PIK3CA is a frequently mutated gene in cancer, including about ~15 to 20% of colorectal cancers (CRC). PIK3CA mutations lead to activation of the PI3K/AKT/mTOR signaling pathway, which plays pivotal roles in tumorigenesis. Here, we investigated the mechanism of resistance of PIK3CA-mutant CRC cell lines to gedatolisib, a dual PI3K/mTOR inhibitor. Out of a panel of 29 CRC cell lines, we identified 7 harboring one or more PIK3CA mutations; of these, 5 and 2 were found to be sensitive and resistant to gedatolisib, respectively. Both of the gedatolisib-resistant cell lines expressed high levels of active glycogen synthase kinase 3-beta (GSK3β) and harbored the same frameshift mutation (c.465_466insC; H155fs*) in TCF7, which encodes a positive transcriptional regulator of the WNT/β-catenin signaling pathway. Inhibition of GSK3β activity in gedatolisib-resistant cells by siRNA-mediated knockdown or treatment with a GSK3β-specific inhibitor effectively reduced the activity of molecules downstream of mTOR and also decreased signaling through the WNT/β-catenin pathway. Notably, GSK3β inhibition rendered the resistant cell lines sensitive to gedatolisib cytotoxicity, both in vitro and in a mouse xenograft model. Taken together, these data demonstrate that aberrant regulation of WNT/β-catenin signaling and active GSK3β induced by the TCF7 frameshift mutation cause resistance to the dual PI3K/mTOR inhibitor gedatolisib. Cotreatment with GSK3β inhibitors may be a strategy to overcome the resistance of PIK3CA- and TCF7-mutant CRC to PI3K/mTOR-targeted therapies.

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Rôle de la voie PI3K-AKT-mTOR dans le cancer et les thérapeutiques antitumorales

Cited by 32 publications

References 32 publications

G-protein-coupled receptor 81 promotes a malignant phenotype in breast cancer through angiogenic factor secretion

G-protein-coupled receptor 81 promotes a malignant phenotype in breast cancer through angiogenic factor secretion

Targeting PI3K/Akt represses Hypoxia inducible factor-1α activation and sensitizes Rhabdomyosarcoma and Ewing’s sarcoma cells for apoptosis

Activation of WNT/β‐catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations

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