Novel Gemini-vitamin D3 analog inhibits tumor cell growth and modulates the Akt/mTOR signaling pathway

2006 ◽  
Vol 100 (4-5) ◽  
pp. 107-116 ◽  
Author(s):  
James O’Kelly ◽  
Milan Uskokovic ◽  
Nathan Lemp ◽  
Jay Vadgama ◽  
H. Phillip Koeffler
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Signaling Pathway ◽  
Vitamin D3 ◽  
Mtor Signaling ◽  
Tumor Cell Growth ◽  
Mtor Signaling Pathway

scholarly journals Downregulation of BZW2 inhibits osteosarcoma cell growth by inactivating the Akt/mTOR signaling pathway

2017 ◽  
Vol 38 (4) ◽  
pp. 2116-2122 ◽  
Author(s):  
Dong-Dong Cheng ◽  
Shi-Jie Li ◽  
Bin Zhu ◽  
Ting Yuan ◽  
Qing-Cheng Yang ◽  
...  
Keyword(s):  
Cell Growth ◽  
Signaling Pathway ◽  
Mtor Signaling ◽  
Osteosarcoma Cell ◽  
Mtor Signaling Pathway

scholarly journals Esterase D stabilizes FKBP25 to suppress mTORC1

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Yuejun Yang ◽  
Xinpeng Chen ◽  
Wen Yao ◽  
Xiaoling Cui ◽  
Na Li ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Signaling Pathway ◽  
Nonspecific Esterase ◽  
Tumor Cell Growth ◽  
Yeast Two Hybrid ◽  
Mtorc1 Signaling ◽  
Two Hybrid

Abstract Background Esterase D (ESD) is a nonspecific esterase that detoxifies formaldehyde. Many reports have stated that ESD activity is associated with a variety of physiological and pathological processes. However, the detailed signaling pathway of ESD remains poorly understood. Methods Considering the advantages of the small chemical molecule, our recent work demonstrated that 4-chloro-2-(5-phenyl-1-(pyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl) phenol (FPD5) activates ESD, and will be a good tool for studying ESD further. Firstly, we determined the interaction between ESD and FK506 binding protein 25 (FKBP25) by yeast two-hybrid assay and co-immunoprecipitation (CO-IP) and analyzed the phosphorylation levels of mTORC1, P70S6K and 4EBP1 by western blot. Furthermore, we used the sulforhodamine B (SRB) and chick chorioallantoic membrane (CAM) assay to analyze cell viability in vitro and in vivo after treatment with ESD activator FPD5. Results We screened FKBP25 as a candidate protein to interact with ESD by yeast two-hybrid assay. Then we verified the interaction between ESD and endogenous FKBP25 or ectopically expressed GFP-FKBP25 by CO-IP. Moreover, the N-terminus (1–90 aa) domain of FKBP25 served as the crucial element for their interaction. More importantly, ESD reduced the K48-linked poly-ubiquitin chains of FKBP25 and thus stabilized cytoplasmic FKBP25. ESD also promoted FKBP25 to bind more mTORC1, suppressing the activity of mTORC1. In addition, ESD suppressed tumor cell growth in vitro and in vivo through autophagy. Conclusions These findings provide novel evidence for elucidating the molecular mechanism of ESD and ubiquitination of FKBP25 to regulate autophagy and cancer cell growth. The ESD/FKBP25/mTORC1 signaling pathway is involved in inhibiting tumor cell growth via regulating autophagy.

scholarly journals Is REDD1 a metabolic double agent? Lessons from physiology and pathology

2020 ◽  
Vol 319 (5) ◽  
pp. C807-C824
Author(s):  
Florian A. Britto ◽  
Karine Dumas ◽  
Sophie Giorgetti-Peraldi ◽  
Vincent Ollendorff ◽  
François B. Favier
Keyword(s):  
Cell Growth ◽  
Signaling Pathway ◽  
Inflammatory Diseases ◽  
Mtor Signaling ◽  
Metabolic Adaptation ◽  
Mtor Signaling Pathway ◽  
Regulate Cell Growth ◽  
Early Biomarker ◽  
Double Agent ◽  
Metabolic Stresses

The Akt/mechanistic target of rapamycin (mTOR) signaling pathway governs macromolecule synthesis, cell growth, and metabolism in response to nutrients and growth factors. Regulated in development and DNA damage response (REDD)1 is a conserved and ubiquitous protein, which is transiently induced in response to multiple stimuli. Acting like an endogenous inhibitor of the Akt/mTOR signaling pathway, REDD1 protein has been shown to regulate cell growth, mitochondrial function, oxidative stress, and apoptosis. Recent studies also indicate that timely REDD1 expression limits Akt/mTOR-dependent synthesis processes to spare energy during metabolic stresses, avoiding energy collapse and detrimental consequences. In contrast to this beneficial role for metabolic adaptation, REDD1 chronic expression appears involved in the pathogenesis of several diseases. Indeed, REDD1 expression is found as an early biomarker in many pathologies including inflammatory diseases, cancer, neurodegenerative disorders, depression, diabetes, and obesity. Moreover, prolonged REDD1 expression is associated with cell apoptosis, excessive reactive oxygen species (ROS) production, and inflammation activation leading to tissue damage. In this review, we decipher several mechanisms that make REDD1 a likely metabolic double agent depending on its duration of expression in different physiological and pathological contexts. We also discuss the role played by REDD1 in the cross talk between the Akt/mTOR signaling pathway and the energetic metabolism.

Inhibition of AKT/mTOR Signaling Pathway Induces Cell Cycle Arrest and Apoptosis in Acute Myelogenous Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2355-2355
Author(s):  
Weina Chen ◽  
Ioannis Grammatikakis ◽  
Jiang Li ◽  
Vassiliki Leventaki ◽  
L. Jeffrey Medeiros ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Cell ◽  
Cell Survival ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Mutational Status ◽  
Tumor Cell Survival ◽  
Dose Dependent

Abstract Acute myelogeneous leukemia (AML) is a heterogeneous disease and includes a subset of neoplasms that harbor activating mutations of the fms-like tyrosine kinase-3 (FLT3) gene. Mutated FLT3 has recently been shown to activate downstream oncogenic pathways including the PI3K/AKT pathway (Scheijen, et al. Oncogene. 23:3338–3349, 2004; Choudhary, et al. Blood. 106:265–273, 2005). It is known that activated AKT mediates its effects, at least in part, through activation of mammalian target of rapamycin (mTOR). However, the potential role of PI3K/AKT/mTOR signaling pathway in tumor cell survival in AML remains largely unknown. We hypothesized that the PI3K/AKT signaling pathway is activated in AML and contributes to tumor cell survival through activation (phosphorylation) of mTOR and its downstream effectors 4EBP1, p70S6K, ribosomal protein S6 (rpS6), and eIF-4E. We used 3 AML cell lines, including MV4-11 and MOLM-13, that are homozygous and heterozygous for mutated FLT3, respectively, as well as U937 (wild-type FLT3). All 3 cell lines expressed activated (serine 473-phosphorylated) AKT (Ser473pAKT), and phosphorylated 4EBP1, p70S6K and rpS6 shown by Western Blot analysis. Treatment of AML cell lines with LY294002, an inhibitor of PI3K, resulted in a dose-dependent decrease of phosphorylation of AKT, mTOR, 4EBP1, p70S6K, and rpS6. This was associated with decreased cell viability as assessed by trypan-blue exclusion assay. Cell death following inhibition of the PI3K/AKT pathway was predominantly attributed to apoptosis as shown by increased annexin V staining assessed by flow cytometry. These changes were associated with downregulation of the anti-apoptotic proteins cFLIP, Mcl-1, and Bcl-XL that are involved in the extrinsic and intrinsic apoptosis. Cell cycle analysis using flow cytometry also showed that inhibition of PI3K resulted in decreased S-phase and increased G1-phase fraction. These cell cycle changes were associated with increased levels of the cyclin-dependent kinase inhibitor p27 and underphosphorylated Rb in a dose-dependent manner. Similar biologic effects, although to a lesser degree, were found after treatment of AML cells with rapamycin, an inhibitor of mTOR. In addition, expression of activated AKT, mTOR, 4EBP1, p70S6K and rpS6 was assessed in AML tumors (n=19) using tissue microarrays of bone marrow samples and immunohistochemical methods. These included tumors with (n=14) and without (n=5) FLT3 mutations. Using a 10% cutoff to define positivity, 13/19 (68%) expressed Ser473pAKT, 16/18 (89%) mTOR, 15/19 (79%) p4E-BP1, 18/19 (95%) p-p70S6K, and 15/18 (83%) p-rpS6. However, no association between expression of activated AKT, or mTOR signaling proteins and FLT3 mutational status was observed. Our study provides first evidence that the AKT/mTOR signaling pathway is activated in AML cell lines and tumors regardless of FLT3 mutational status. The AKT/mTOR signaling pathway may contribute to cell cycle progression and tumor cell survival in AML. Inhibition of this oncogenic pathway represents a potential target for therapy in patients with AML.

Vitamin-D3 derivatives and breast-tumor cell growth: Effect on intracellular calcium and apoptosis

1995 ◽  
Vol 61 (6) ◽  
pp. 806-811 ◽  
Author(s):  
Brigitte Vandewalle ◽  
Louis Hornez ◽  
Nicole Wattez ◽  
Françoise Revillion ◽  
Jean Lefebvre
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Intracellular Calcium ◽  
Vitamin D3 ◽  
Breast Tumor ◽  
Growth Effect ◽  
Tumor Cell Growth ◽  
Breast Tumor Cell

scholarly journals Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1

2021 ◽  
Vol 11 ◽  
Author(s):  
Wenpeng Cao ◽  
Zhirui Zeng ◽  
Runsang Pan ◽  
Hao Wu ◽  
Xiangyan Zhang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Growth ◽  
Western Blot ◽  
Signaling Pathway ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Cell Growth And Migration ◽  
And Migration ◽  
The Stability

BackgroundHypoxia is associated with the development of pancreatic cancer (PC). However, genes associated with hypoxia response and their regulatory mechanism in PC cells were unclear. The current study aims to investigate the role of the hypoxia associated gene fucosyltransferase 11 (FUT11) in the progression of PC.MethodsIn the preliminary study, bioinformatics analysis predicted FUT11 as a key hypoxia associated gene in PC. The expression of FUT11 in PC was evaluated using quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry. The effects of FUT11 on PC cells proliferation and migration under normoxia and hypoxia were evaluated using Cell Counting Kit 8, 5-ethynyl-2’-deoxyuridine (EDU) assay, colony formation assay and transwell assay. The effects of FUT11 in vivo was examined in mouse tumor models of liver metastasis and subcutaneous xenograft. Furthermore, Western blot, luciferase assay and immunoprecipitation were performed to explore the regulatory relationship among FUT11, hypoxia-inducible factor 1α (HIF1α) and pyruvate dehydrogenase kinase 1 (PDK1) in PC.ResultsFUT11 was markedly increased of PC cells with hypoxia, upregulated in the PC clinical tissues, and predicted a poor outcome of PC patients. Inhibition of FUT11 reduced PC cell growth and migratory ability of PC cells under normoxia and hypoxia conditions in vitro, and growth and tumor cell metastasis in vivo. FUT11 bound to PDK1 and regulated the expression PDK1 under normoxia and hypoxia. FUT11 interacted with PDK1 and decreased the ubiquitination of PDK1, lead to the activation of AKT/mTOR signaling pathway. FUT11 knockdown significantly increased the degradation of PDK1 under hypoxia, while treatment with MG132 can relieve the degradation of PDK1 induced by FUT11 knockdown. Overexpression of PDK1 in PC cells under hypoxia conditions reversed the suppressive impacts of FUT11 knockdown on PC cell growth and migration. In addition, HIF1α bound to the promoter of FUT11 and increased its expression, as well as co-expressed with FUT11 in PC tissues. Furthermore, overexpression of FUT11 partially rescued the suppressive effects of HIF1α knockdown on PC cell growth and migration in hypoxia condition.ConclusionOur data implicate that hypoxia-induced FUT11 contributes to proliferation and metastasis of PC by maintaining the stability of PDK1, thus mediating activation of AKT/mTOR signaling pathway, and suggest that FUT11 could be a novel and effective target for the treatment of pancreatic cancer.

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