Effects of tetrandrine and caffeine on cell viability and expression of mammalian target of rapamycin, phosphatase and tensin homolog, histone deacetylase 1, and histone acetyltransferase in glioma cells

Although preclinical work with rapalogs suggests potential in treatment of multiple myeloma (MM), they have been less successful clinically. These drugs allostearically inhibit the mammalian target of rapamycin kinase primarily curtailing activity of the target of rapamycin complex (TORC)1. To assess if the mammalian target of rapamycin within the TORC2 complex could be a better target in MM, we tested a new agent, pp242, which prevents activation of TORC2 as well as TORC1. Although comparable to rapamycin against phosphorylation of the TORC1 substrates p70S6kinase and 4E-BP-1, pp242 could also inhibit phosphorylation of AKT on serine 473, a TORC2 substrate, while rapamycin was ineffective. pp242 was also more effective than rapamycin in achieving cytoreduction and apoptosis in MM cells. In addition, pp242 was an effective agent against primary MM cells in vitro and growth of 8226 cells in mice. Knockdown of the TORC2 complex protein, rictor, was deleterious to MM cells further supporting TORC2 as the critical target for pp242. TORC2 activation was frequently identified in primary specimens by immunostaining for AKT phosphorylation on serine 473. Potential mechanisms of up-regulated TORC2 activity in MM were stimulation with interleukin-6 or insulin-like growth factor 1, and phosphatase and tensin homolog or RAS alterations. Combining pp242 with bortezomib led to synergistic anti-MM effects. These results support TORC2 as a therapeutic target in MM.

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Effect of 6-Shogaol on the Glucose Uptake and Survival of HT1080 Fibrosarcoma Cells

Pharmaceuticals ◽

10.3390/ph12030131 ◽

2019 ◽

Vol 12 (3) ◽

pp. 131 ◽

Cited By ~ 1

Author(s):

Angie C. Romero-Arias ◽

Luis G. Sequeda-Castañeda ◽

Andres F. Aristizábal-Pachón ◽

Ludis Morales

Keyword(s):

Cell Viability ◽

Glucose Uptake ◽

Tumor Cells ◽

Southern China ◽

Mammalian Target Of Rapamycin ◽

Ros Production ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

P Proteins ◽

Phosphoinositide 3 Kinase

Ginger is a plant that is native to southern China. In the last decade and research on the components of ginger has significantly increased; of these components, 6-shogaol exhibits the greatest potential antitumor capacity. However, the molecular mechanism through which 6-shogaol exerts its effects has not yet been elucidated. In this study, the effect of 6-shogaol on tumor cells that were derived from human fibrosarcoma (HT1080) was evaluated. Cell viability was determined by a (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT assay testing different concentrations of 6-shogaol (2.5–150 μM). Subsequently, the effect of 6-shogaol on reactive oxygen species (ROS) production, glucose uptake, and protein expression of the signaling pathway phosphatase and tensin homolog/ protein kinase B /mammalian target of rapamycin (PTEN/Akt/mTOR) was measured. 6-Shogaol reduced the viability of the tumor cells and caused an increase in ROS production, which was attenuated with the addition of N-acetylcysteine, and the recovery of cell viability was observed. The increase in ROS production in response to 6-shogaol was associated with cell death. Similarly, glucose uptake decreased with incremental concentrations of 6-shogaol, and an increase in the expression of mTOR-p and Akt-p proteins was observed; PTEN was active in all the treatments with 6-shogaol. Thus, the results suggest that cells activate uncontrolled signaling pathways, such as phosphoinositide 3-kinase (PI3K)/Akt/mTOR, among other alternative mechanisms of metabolic modulation and of survival in order to counteract the pro-oxidant effect of 6-shogaol and the decrease in glucose uptake. Interestingly, a differential response was observed when non-cancerous cells were treated with 6-shogaol.

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Mammalian target of rapamycin (mTOR; FRAP; RAFT1); phosphatase and tensin homolog deleted on chromosome ten (PTEN; MMAC1; TEP1); tumor protein p53 (TP53; p53)

Science-Business eXchange ◽

10.1038/scibx.2009.479 ◽

2009 ◽

Vol 2 (12) ◽

pp. 479-479

Keyword(s):

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Protein P53 ◽

Tumor Protein P53

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Unrestrained Mammalian Target of Rapamycin Complexes 1 and 2 Increase Expression of Phosphatase and Tensin Homolog Deleted on Chromosome 10 to Regulate Phosphorylation of Akt Kinase

Journal of Biological Chemistry ◽

10.1074/jbc.m111.246397 ◽

2011 ◽

Vol 287 (6) ◽

pp. 3808-3822 ◽

Cited By ~ 28

Author(s):

Falguni Das ◽

Nandini Ghosh-Choudhury ◽

Nirmalya Dey ◽

Chandi Charan Mandal ◽

Lenin Mahimainathan ◽

...

Keyword(s):

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Chromosome 10 ◽

Akt Kinase ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog

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Lupeol Inhibits Proliferation and Promotes Apoptosis of Ovarian Cancer Cells by Inactivating Phosphoinositide-3-Kinase/Protein Kinase B/ Mammalian Target of Rapamycin Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:206-210 ◽

2020 ◽

Vol 19 (2) ◽

pp. 206-210

Author(s):

Feng Chen ◽

Bei Zhang

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Protein Kinase ◽

Cell Viability ◽

Cancer Cells ◽

Protein Kinase B ◽

Mammalian Target Of Rapamycin ◽

Target Of Rapamycin ◽

Ovarian Cancer Cells ◽

Phosphoinositide 3 Kinase

Lupeol exhibits multiple pharmacological activities including, anticancerous, anti-inflammatory, and antioxidant. The aim of this study was to explore the anticancerous activity of lupeol on ovarian cancer cells and examine its mechanism of action. To this end, increasing concentrations of lupeol on cell viability, cell cycle, and apoptosis in Caov-3 cells were evaluated. Lupeol inhibited cell viability, induced G1 phase arrest in cell cycle, increased cell apoptosis, and inhibited the ratio of phospho-Akt/protein kinase B and phospho-mammalian target of rapamycin/mammalian target of rapamycin. In conclusion, these data suggest that lupeol may play a therapeutic role in ovarian cancer.

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Contribution of mTOR and PTEN to Radioresistance in Sporadic and NF2-Associated Vestibular Schwannomas: A Microarray and Pathway Analysis

Cancers ◽

10.3390/cancers12010177 ◽

2020 ◽

Vol 12 (1) ◽

pp. 177 ◽

Cited By ~ 1

Author(s):

Isabel Gugel ◽

Florian H. Ebner ◽

Florian Grimm ◽

Stefan Czemmel ◽

Frank Paulsen ◽

...

Keyword(s):

Pathway Analysis ◽

Radiation Treatment ◽

Mammalian Target Of Rapamycin ◽

Neurofibromatosis Type ◽

P Value ◽

Mtor Inhibition ◽

Phosphatase And Tensin Homolog ◽

Molecular Alterations ◽

Tensin Homolog ◽

Systemic Treatments

The use of radiation treatment has increased for both sporadic and neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS). However, there are a subset of radioresistant tumors and systemic treatments that are seldom used in these patients. We investigated molecular alterations after radiation in three NF2-associated and five sporadically operated recurrent VS after primary irradiation. We compared these findings with 49 non-irradiated (36 sporadic and 13 NF2-associated) VS through gene-expression profiling and pathway analysis. Furthermore, we stained the key molecules of the distinct pathway by immunohistochemistry. A total of 195 differentially expressed genes in sporadic and NF2-related comparisons showed significant differences based on the criteria of p value < 0.05 and a two-fold change. These genes were involved in pathways that are known to be altered upon irradiation (e.g., mammalian target of rapamycin (mTOR), phosphatase and tensin homolog (PTEN) and vascular endothelial growth factor (VEGF) signaling). We observed a combined downregulation of PTEN signaling and an upregulation of mTOR signaling in progressive NF2-associated VS after irradiation. Immunostainings with mTOR and PTEN antibodies confirmed the respective molecular alterations. Taken together, mTOR inhibition might be a promising therapeutic strategy in NF2-associated VS progress after irradiation.

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PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine?

Genes ◽

10.3390/genes11070719 ◽

2020 ◽

Vol 11 (7) ◽

pp. 719

Author(s):

Nicola Fusco ◽

Elham Sajjadi ◽

Konstantinos Venetis ◽

Gabriella Gaudioso ◽

Gianluca Lopez ◽

...

Keyword(s):

Solid Tumors ◽

Mammalian Target Of Rapamycin ◽

Genetic Alterations ◽

Phosphatase And Tensin Homolog ◽

Cancer Management ◽

Tensin Homolog ◽

Current State ◽

Tumor Immune Microenvironment ◽

Damage Response ◽

Phosphoinositide 3 Kinase

Alterations in the tumor suppressor phosphatase and tensin homolog (PTEN) occur in a substantial proportion of solid tumors. These events drive tumorigenesis and tumor progression. Given its central role as a downregulator of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, PTEN is deeply involved in cell growth, proliferation, and survival. This gene is also implicated in the modulation of the DNA damage response and in tumor immune microenvironment modeling. Despite the actionability of PTEN alterations, their role as biomarkers remains controversial in clinical practice. To date, there is still a substantial lack of validated guidelines and/or recommendations for PTEN testing. Here, we provide an update on the current state of knowledge on biologic and genetic alterations of PTEN across the most frequent solid tumors, as well as on their actual and/or possible clinical applications. We focus on possible tailored schemes for cancer patients’ clinical management, including risk assessment, diagnosis, prognostication, and treatment.

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BMI1 promotes cardiac fibrosis in ischemia-induced heart failure via the PTEN-PI3K/Akt-mTOR signaling pathway

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00487.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. H61-H69 ◽

Cited By ~ 11

Author(s):

Wenbo Yang ◽

Zhijun Wu ◽

Ke Yang ◽

Yanxin Han ◽

Yanjia Chen ◽

...

Keyword(s):

Cardiac Fibrosis ◽

Mammalian Target Of Rapamycin ◽

Phosphatidylinositol 3 Kinase ◽

Phosphatase And Tensin Homolog ◽

B Lymphoma ◽

Tensin Homolog ◽

And Migration ◽

Proliferation And Migration

Cardiac fibrosis has been known to play an important role in the etiology of heart failure after myocardial infarction (MI). B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a transcriptional repressor, is important for fibrogenesis in the kidneys. However, the effect of BMI1 on ischemia-induced cardiac fibrosis remains unclear. BMI1 was strongly expressed in the infarct region 1 wk post-MI in mice and was detected by Western blot and histological analyses. Lentivirus-mediated overexpression of BMI1 significantly promoted cardiac fibrosis, worsened cardiac function 4 wk after the intervention in vivo, and enhanced the proliferation and migration capabilities of fibroblasts in vitro , whereas downregulation of BMI1 decreased cardiac fibrosis and prevented cardiac dysfunction in mice 4 wk post-MI in vivo. Furthermore, upregulated BMI1 inhibited phosphatase and tensin homolog (PTEN) expression, enhanced phosphatidylinositol 3-kinase (PI3K) expression, and increased the phosphorylation level of Akt and mammalian target of rapamycin (mTOR) in mice 4 wk after lentiviral infection, which was in accordance with the changes seen in their infarcted myocardial tissues. At the same time, the effects of BMI1 on cardiac fibroblasts were reversed in vitro when these cells were exposed to NVP-BEZ235, a dual-kinase (PI3K/mTOR) inhibitor. In conclusion, BMI1 is associated with cardiac fibrosis and dysfunction after MI by regulating cardiac fibroblast proliferation and migration, and these effects could be partially explained by the regulation of the PTEN-PI3K/Akt-mTOR pathway. NEW & NOTEWORTHY Ischemia-induced B lymphoma Mo-MLV insertion region 1 homolog (BMI1) significantly promoted cardiac fibrosis and worsened cardiac function in vivo, whereas downregulation of BMI1 decreased cardiac fibrosis and prevented cardiac dysfunction in myocardial infarcted mice. BMI1 also enhanced proliferation and migration capabilities of fibroblasts in vitro; these effects were reversed by NVP-BEZ235. Effects of BMI1 on cardiac fibrosis could be partially explained by regulation of the phosphatase and tensin homolog-phosphatidylinositol 3-kinase/Akt-mammalian target of rapamycin pathway.

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Conjunctival Melanoma: Genetic and Epigenetic Insights of a Distinct Type of Melanoma

International Journal of Molecular Sciences ◽

10.3390/ijms20215447 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5447 ◽

Cited By ~ 6

Author(s):

Rossi ◽

Schinzari ◽

Maiorano ◽

Pagliara ◽

Di Stefani ◽

...

Keyword(s):

Cutaneous Melanoma ◽

Mammalian Target Of Rapamycin ◽

Heat Shock Protein 90 ◽

Distinct Type ◽

Biological Behavior ◽

Conjunctival Melanoma ◽

Phosphatase And Tensin Homolog ◽

Pten Loss ◽

Tensin Homolog ◽

Neurofibromin 1

Conjunctival melanoma (CjM) is a rare, primary cancer of the ocular region. Genetic and epigenetic characteristics of conjunctival melanoma have not been completely elucidated yet. Conjunctival melanoma presents similarities with cutaneous melanoma, with substantial differences in the biological behavior. We reviewed the genetic and epigenetic insights of CjM involved in invasion and metastatic spread. CjM is commonly characterized by mutations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF), neurofibromin 1 (NF1) and telomerase reverse transcriptase (TERT), high expression of mammalian target of rapamycin (mTOR) and heat shock protein 90 (HSP90), frequent phosphatase and tensin homolog (PTEN) loss and upregulation of specific miRNAs. These features should identify CjM as a distinct subset of melanoma with its own profile, which is more similar to cutaneous melanoma than mucosal melanoma and remarkably different from uveal melanoma.

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