scholarly journals Lysophosphatidic Acid Receptor 5 (LPAR5) Plays a Significance Role in Papillary Thyroid Cancer via Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin (mTOR) Pathway

2020 ◽  
Vol 26 ◽  
Author(s):  
Cheng-Yong Wu ◽  
Chen Zheng ◽  
Er-Jie Xia ◽  
Rui-Da Quan ◽  
Jing Hu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Lysophosphatidic Acid ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Papillary Thyroid ◽  
Phosphatidylinositol 3 Kinase ◽  
Acid Receptor ◽  
Lysophosphatidic Acid Receptor

Oncogenic mutations in PI3K/AKT/mTOR pathway effectors associate with worse prognosis in BRAFV600E-driven papillary thyroid cancer patients

2021 ◽  
pp. clincanres.0874.2021
Author(s):  
Theodora Pappa ◽  
Sara Ahmadi ◽  
Ellen Marqusee ◽  
Hannah L. Johnson ◽  
Matthew A. Nehs ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Patients ◽  
Papillary Thyroid Cancer ◽  
Mtor Pathway ◽  
Papillary Thyroid ◽  
Oncogenic Mutations ◽  
Worse Prognosis

scholarly journals Prolactin activates mammalian target-of-rapamycin through phosphatidylinositol 3-kinase and stimulates phosphorylation of p70S6K and 4E-binding protein-1 in lymphoma cells

2006 ◽  
Vol 190 (2) ◽  
pp. 307-312 ◽  
Author(s):  
Jessica D Bishop ◽  
Wei Lun Nien ◽  
Shauna M Dauphinee ◽  
Catherine K L Too
Keyword(s):  
Binding Protein ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Lymphoma Cells ◽  
Nb2 Cells ◽  
Initiation Of Translation ◽  
Phosphatidylinositol 3

Mitogens activate the mammalian target-of-rapamycin (mTOR) pathway through phosphatidylinositol 3-kinase (PI3K). The activated mTOR kinase phosphorylates/ activates ribosomal protein S6 kinase (p70S6K) and phosphorylates/inactivates eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), resulting in the initiation of translation and cell-cycle progression. The prolactin receptor signaling cascade has been implicated in crosstalk with the mTOR pathway, but whether prolactin (PRL) directly activates mTOR is not known. This study showed that PRL stimulated the phosphorylation of mTOR, p70S6K, Akt, and Jak2 kinases in a dose- and time-dependent manner in PRL-dependent rat Nb2 lymphoma cells. PRL-stimulated phosphorylation of mTOR was detected as early as 10 min, closely following the phosphorylation of Akt (upstream of mTOR), but preceding that of the downstream p70S6K. PRL activation of mTOR was inhibited by rapamycin (mTOR inhibitor), LY249002, and wortmannin (P13K inhibitors), but not by AG490 (Jak2 inhibitor), indicating that it was mediated by the P13K/Akt, but not Jak2, pathway. PRL also stimulated phosphorylation of 4E-BP1 in Nb2 cells. PRL-induced phosphorylation of p70S6K and 4E-BP1 was inhibited by rapamycin, but not by okadaic acid (inhibitor of protein phosphatase, PP2A). PRL induced a transient interaction between p70S6K and the catalytic subunit of PP2A (PP2Ac) in 1 and 2 h, whereas a PP2Ac–4E-BP1 complex was constitutively present in quiescent and PRL-treated Nb2 cells. These results suggested that p70S6K and 4E-BP1 were substrates of PP2A and the inhibition of mTOR promoted their dephosphorylation by PP2A. In summary, PRL-stimulated phosphorylation of mTOR is mediated by PI3K. PRL-activated mTOR may phosphorylate p70S6K and 4E-BP1 by restraining PP2A.

scholarly journals Forkhead Box Protein O1 Negatively Regulates Skeletal Myocyte Differentiation through Degradation of Mammalian Target of Rapamycin Pathway Components

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 1407-1414 ◽  
Author(s):  
Ai-Luen Wu ◽  
Jeong-Ho Kim ◽  
Chongben Zhang ◽  
Terry G. Unterman ◽  
Jie Chen
Keyword(s):  
Myogenic Differentiation ◽  
Mammalian Target Of Rapamycin ◽  
Akt Signaling ◽  
Nutrient Sensing ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Phosphatidylinositol 3 Kinase ◽  
Forkhead Box ◽  
Myocyte Differentiation ◽  
Phosphatidylinositol 3

The forkhead transcription factor forkhead box protein O1 (FoxO1), a downstream target of phosphatidylinositol 3-kinase/Akt signaling, has been reported to suppress skeletal myocyte differentiation, but the mechanism by which FoxO1 regulates myogenesis is not fully understood. We have previously demonstrated that a nutrient-sensing mammalian target of rapamycin (mTOR) pathway controls the autocrine production of IGF-II and the subsequent phosphatidylinositol 3-kinase/Akt signaling downstream of IGF-II in myogenesis. Here we report a regulatory loop connecting FoxO1 to the mTOR pathway. Inducible activation of a FoxO1 active mutant in the C2C12 mouse myoblasts blocks myogenic differentiation at an early stage and meanwhile leads to proteasome-dependent degradation of a specific subset of components in the mTOR signaling network, including mTOR, raptor, tuberous sclerosis complex 2, and S6 protein kinase 1. This function of FoxO1 requires new protein synthesis, consistent with the idea that a transcriptional target of FoxO1 may be responsible for the degradation of mTOR. We further show that active FoxO1 inhibits IGF-II expression at the transcriptional activation level, through the modulation of mTOR protein levels. Moreover, the addition of exogenous IGF-II fully rescues myocyte differentiation from FoxO inhibition. Taken together, we propose that the mTOR-IGF-II pathway is a major mediator of FoxO’s inhibitory function in skeletal myogenesis.

scholarly journals Dual Inhibition of Mitogen-Activated Protein Kinase Kinase and Mammalian Target of Rapamycin in Differentiated and Anaplastic Thyroid Cancer

2009 ◽  
Vol 23 (11) ◽  
pp. 1937-1937
Author(s):  
Ning Jin ◽  
Tianyun Jiang ◽  
D. Marc Rosen ◽  
Barry D. Nelkin ◽  
Douglas W. Ball
Keyword(s):  
Thyroid Cancer ◽  
Growth Inhibition ◽  
Differentiated Thyroid Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Xenograft Model ◽  
Anaplastic Thyroid Cancer ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Mtor Inhibition ◽  
Pathway Inhibition

ABSTRACT Context Differentiated thyroid cancer and anaplastic thyroid cancer tumors frequently have activation of the ras/raf /MAPK kinase (MEK)/ERK and phosphatidylinositol 3-kinase (PI-3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathways. Objective The objective of the study was to investigate the efficacy of MEK and mTOR inhibitors in preclinical thyroid cancer treatment models with defined mutation status. Experimental Design The MEK inhibitor AZD6244 (ARRY-142886) and mTOR inhibitor rapamycin were tested separately and in combination in 10 differentiated thyroid cancer and anaplastic thyroid cancer cell lines and in a xenograft model for evidence of pathway inhibition, growth inhibition, apoptosis, and long-range adaptation and resistance. Results Seven of 10 tested lines had evidence of significant basal activity of the PI-3K/AKT/mTOR pathway, with elevated phosphorylated AKT and phosphorylated p70 S6 kinase. Activation of ras/RAF/MEK/ERK was equally common in this panel. All 10 lines exhibited better than 60% growth inhibition with combined MEK and mTOR inhibition, including lines with BRAF, Ret-PTC, ras, and PTEN mutations. Rapamycin or AZD6244 alone achieved this threshold in six and two lines, respectively. Dual-pathway inhibition in the Ret-PTC mutant cell line TPC1 caused an intense G1 arrest in cell culture and reversible cytostatic inhibition in a xenograft model. We did not observe significant feedback up-regulation of AKT activation in either acute or prolonged exposures. Conclusion These preclinical results support the inclusion of thyroid cancer patients in early-phase clinical trials combining ras/RAF/MEK/ERK and PI-3K/AKT/mTOR pathway inhibition.

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