Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

mTOR complex 2 (mTORC2) contains the mammalian target of rapamycin (mTOR) kinase and the Rictor regulatory protein and phosphorylates Akt. Whether this function of mTORC2 is critical for cancer progression is unknown. Here, we show that transformed human prostate epithelial cells lacking PTEN require mTORC2 to form tumors when injected into nude mice. Furthermore, we find that Rictor is a haploinsufficient gene and that deleting one copy protects Pten heterozygous mice from prostate cancer. Finally, we show that the development of prostate cancer caused by Pten deletion specifically in prostate epithelium requires mTORC2, but that for normal prostate epithelial cells, mTORC2 activity is nonessential. The selective requirement for mTORC2 in tumor development suggests that mTORC2 inhibitors may be of substantial clinical utility.
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PMID:mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. 1918 49

Angiogenin (ANG), originally identified as an angiogenic ribonuclease, has recently been shown to play a direct role in prostate cancer cell proliferation by mediating rRNA transcription. ANG is up-regulated in human prostate cancer and is the most significantly up-regulated gene in AKT-driven prostate intraepithelial neoplasia (PIN) in mice. Enhanced cell proliferation in the PIN lesions requires increased ribosome biogenesis, a multistep process involving an orchestrated production of ribosomal proteins and rRNA. AKT is known to enhance ribosomal protein production through the mammalian target of rapamycin pathway. However, it was unknown how rRNA is proportionally increased. Here, we report that ANG is essential for AKT-driven PIN formation and survival. We showed that up-regulation of ANG in the AKT-overexpressing mouse prostates is an early and lasting event. It occurs before PIN initiation and lasts beyond PIN is fully developed. Knocking down ANG expression by intraprostate injection of lentivirus-mediated ANG-specific small interfering RNA prevents AKT-induced PIN formation without affecting AKT expression and its signaling through the mammalian target of rapamycin pathway. Neomycin, an aminoglycoside that blocks nuclear translocation of ANG, and N65828, a small-molecule enzymatic inhibitor of the ribonucleolytic activity of ANG, both prevent AKT-induced PIN formation and reverse established PIN. They also decrease nucleolar organizer region, restore cell size, and normalize luminal architectures of the prostate despite continuous activation of AKT. All three types of the ANG inhibitor suppress rRNA transcription of the prostate luminal epithelial cells and inhibit AKT-induced PIN, indicating an essential role of ANG in AKT-mediated cell proliferation and survival.
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PMID:Angiogenin-stimulated rRNA transcription is essential for initiation and survival of AKT-induced prostate intraepithelial neoplasia. 1925 15

The regulation of androgen receptor (AR) expression in prostate cancer is still poorly understood. The activation of the epidermal growth factor receptor (EGFR) in prostate cancer cells was previously shown to lower AR expression by a rapamycin-sensitive, posttranscriptional mechanism involving the AR mRNA 5'-untranslated region (5'-UTR). In a search for an intermediate within the EGFR/phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway that regulates AR at this site, we identified the nucleic acid-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNP-K), by mass spectrometric analysis of Akt immune complexes from lipid raft-enriched subcellular fractions. We show here that hnRNP-K is a novel inhibitor of AR mRNA translation that regulates androgen-responsive gene expression and prostate cancer cell proliferation. A functional hnRNP-K binding site involved in down-regulating AR protein levels was identified in the AR mRNA 5'-UTR. Further analysis revealed that hnRNP-K is also able to inhibit AR translation in the absence of the 5'-UTR, consistent with the presence of additional predicted hnRNP-K binding sites within the AR open reading frame and in the 3'-UTR. Immunohistochemical analysis of a human prostate cancer tissue microarray revealed an inverse correlation between hnRNP-K expression and AR protein levels in organ-confined prostate tumors and a substantial decline in cytoplasmic hnRNP-K in metastases, despite an overall increase in hnRNP-K levels in metastatic tumors. These data suggest that translational inhibition of AR by hnRNP-K may occur in organ-confined tumors but possibly at a reduced level in metastases. HnRNP-K is the first protein identified that directly interacts with and regulates the AR translational apparatus.
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PMID:Heterogeneous nuclear ribonucleoprotein K is a novel regulator of androgen receptor translation. 1925 14

A large number of novel therapeutics is currently undergoing clinical evaluation for the treatment of prostate cancer, and small molecule signal transduction inhibitors are a promising class of agents. These inhibitors have recently become a standard therapy in renal cell carcinoma and offer significant promise in prostate cancer. Through an understanding of the key pathways involved in prostate cancer progression, a rational drug design can be aimed at the molecules critical to cellular signaling. This may enable administration of selective therapies based on the expression of molecular targets, more appropriately individualizing treatment for prostate cancer patients. One pathway with a prominent role in prostate cancer is the PI3K/Akt/mTOR pathway. Current estimates suggest that PI3K/Akt/mTOR signaling is upregulated in 30-50% of prostate cancers, often through loss of PTEN. Molecular changes in the PI3K/Akt/mTOR signaling pathway have been demonstrated to differentiate benign from malignant prostatic epithelium and are associated with increasing tumor stage, grade, and risk of biochemical recurrence. Multiple inhibitors of this pathway have been developed and are being assessed in the laboratory and in clinical trials, with much attention focusing on mTOR inhibition. Current clinical trials in prostate cancer are assessing efficacy of mTOR inhibitors in combination with multiple targeted or traditional chemotherapies, including bevacizumab, gefitinib, and docetaxel. Completion of these trials will provide substantial information regarding the importance of this pathway in prostate cancer and the clinical implications of its targeted inhibition. In this article we review the data surrounding PI3K/Akt/mTOR inhibition in prostate cancer and their clinical implications.
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PMID:Targeted therapy for advanced prostate cancer: inhibition of the PI3K/Akt/mTOR pathway. 1927 62

Short interfering RNA targeting ILK (ILK siRNA) could be used to treat patients with cancers where constitutive activation of the AKT/PI3K pathway is prominent (e.g., those cancers lack functional PTEN). It is generally believed that siRNA therapeutics will require the use of delivery systems and lipid-based formulations containing cationic lipids (CLs) are a viable option. However, CLs are known to be toxic and exposure to CLs can influence cell survival pathways. This study characterized how CLs combine with ILK siRNA to influence the AKT/PI3K pathway. Using PTEN-negative cell lines (PC3 castration-insensitive prostate cancer cells and U251 glioma cancer cells), the influence of CLs on the downstream consequences of ILK silencing was determined. When comparing nucleofection (an electroporation method that does not require the use of CLs) and CLs as means to deliver ILK siRNA, a 12- to 30-fold increase in siRNA delivery was achieved when using a CL formulation, yet ILK suppression was less efficient. Importantly, time-dependent signaling consequences associated with ILK silencing, including suppression of phosphorylated (serine 473)-AKT and changes in mTOR expression, were observed independently of ILK suppression when the target cells were exposed to cationic lipids following nucleofection-based delivery of ILK siRNA.
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PMID:siRNA-mediated integrin-linked kinase suppression: nonspecific effects of siRNA/cationic liposome complexes trigger changes in the expression of phosphorylated-AKT and mTOR independently of ILK silencing. 1928 9

Increasing interest in the use of phytochemicals to reduce prostate cancer led us to investigate 2 potential agents, curcumin and resveratrol as preventive agents. However, there is concern about the bioavailability of these agents pertinent to the poor absorption and thereby limiting its clinical use. With the view to improve their bioavailability, we used the liposome encapsulated curcumin, and resveratrol individually and in combination in male B6C3F1/J mice. Further, we examined the chemopreventive effect of liposome encapsulated curcumin and resveratrol in combination in prostate-specific PTEN knockout mice. In vitro assays using PTEN-CaP8 cancer cells were performed to investigate the combined effects curcumin with resveratrol on (i) cell growth, apoptosis and cell cycle (ii) impact on activated p-Akt, cyclin D1, m-TOR and androgen receptor (AR) proteins involved in tumor progression. HPLC analysis of serum and prostate tissues showed a significant increase in curcumin level when liposome encapsulated curcumin coadministered with liposomal resveratrol (p < 0.001). Combination of liposomal forms of curcumin and resveratrol significantly decreased prostatic adenocarcinoma in vivo (p < 0.001). In vitro studies revealed that curcumin plus resveratrol effectively inhibit cell growth and induced apoptosis. Molecular targets activated due to the loss of phosphatase and tensin homolog (PTEN) including p-Akt, cyclin D1, mammalian target of rapamycin and AR were downregulated by these agents in combination. Findings from this study for the first time provide evidence on phytochemicals in combination to enhance chemopreventive efficacy in prostate cancer. These findings clearly suggest that phytochemicals in combination may reduce prostate cancer incidence due to the loss of the tumor suppressor gene PTEN.
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PMID:Liposome encapsulation of curcumin and resveratrol in combination reduces prostate cancer incidence in PTEN knockout mice. 1961 59

Phenethyl isothiocyanate (PEITC) is a promising cancer chemopreventive agent but the mechanism of its anticancer effect is not fully understood. We now show, for the first time, that PEITC treatment triggers Atg5-dependent autophagic and apoptotic cell death in human prostate cancer cells. Exposure of PC-3 (androgen independent, p53 null) and LNCaP (androgen responsive, wild-type p53) human prostate cancer cells to PEITC resulted in several specific features characteristic of autophagy, including appearance of membranous vacuoles, formation of acidic vesicular organelles, and cleavage and recruitment of microtubule-associated protein 1 light chain 3 (LC3) to autophagosomes. A normal human prostate epithelial cell line (PrEC) was markedly more resistant toward PEITC-mediated cleavage and recruitment of LC3 compared with prostate cancer cells. Although PEITC treatment suppressed activating phosphorylations of Akt and mammalian target of rapamycin (mTOR), which are implicated in regulation of autophagy by different stimuli, processing and recruitment of LC3 was only partially/marginally reversed by ectopic expression of constitutively active Akt or overexpression of mTOR-positive regulator Rheb. The PEITC-mediated apoptotic DNA fragmentation was significantly attenuated in the presence of a pharmacologic inhibitor of autophagy (3-methyl adenine). Transient transfection of LNCaP and PC-3 cells with Atg5-specific small interfering RNA conferred significant protection against PEITC-mediated autophagy as well as apoptotic DNA fragmentation. A xenograft model using PC-3 cells and Caenorhabditis elegans expressing a lgg-1:GFP fusion protein provided evidence for occurrence of PEITC-induced autophagy in vivo. In conclusion, the present study indicates that Atg5 plays an important role in regulation of PEITC-induced autophagic and apoptotic cell death.
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PMID:Atg5 regulates phenethyl isothiocyanate-induced autophagic and apoptotic cell death in human prostate cancer cells. 1933 71

mTOR pathway inhibitors, specifically rapamycin and its derivatives, are promising therapeutics that targets downstream pathways including protein translation. We examined the effects of a series of inhibitors targeting various pathways on ribosomal polysome distribution, overall translation rates, and translation of specific mRNAs in the bone derived prostate cancer cell line, C4-2B. Treatment with either rapamycin, PD98059 or LY294002 failed to change the distribution of polysomes in sucrose gradients. Although no change in the accumulation of heavy polysomes was observed, there was an overall decrease in the rate of translation caused by treatment with rapamycin or LY294002. Inhibiting the MAPK pathway with PD98059 decreased overall translation by 20%, but had no effect on mRNAs containing a 5' terminal oligopyrimidine tract (TOP) sequences or those with complex 5' UTRs. In contrast, treatment with rapamycin for 24 h reduced overall translation by approximately 45% and affected the translation of mRNAs with complex 5' UTRs, specifically VEGF and HIF1alpha. After 24 h, LY294002 treatment alone decreased overall translation by 60%, more than was observed with rapamycin. Although LY294002 and similar inhibitors are effective at blocking prostate cancer cell growth, they act upstream of AKT and PTEN and cancer cells can find a way to bypass this inhibition. Thus, we propose that inhibiting downstream targets such as mTOR or targets of mTOR will provide rational approaches to developing new combination therapies focused on reducing growth of prostate cancer after arrival in the bone environment.
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PMID:Rapamycin selectively reduces the association of transcripts containing complex 5' UTRs with ribosomes in C4-2B prostate cancer cells. 1934 4

PTEN haploinsufficiency is common in hormone-sensitive prostate cancer, though the incidence of genomic deletion and its downstream effects have not been elucidated in clinical samples of hormone refractory prostate cancer (HRPC). Progression to androgen independence is pivotal in prostate cancer and mediated largely by the androgen receptor (AR). Since this process is distinct from metastatic progression, we examined alterations of the PTEN gene in locally advanced recurrent, non-metastatic human HRPC tissues. Retrospective analyses of PTEN deletion status were correlated with activated downstream phospho-Akt (p-Akt) pathway proteins and with the androgen receptor. The prevalence of PTEN genomic deletions in transurethral resection samples of 59 HRPC patients with known clinical outcome was assessed by four-colour FISH analyses. FISH was performed using six BAC clones spanning both flanking PTEN genomic regions and the PTEN gene locus, and a chromosome 10 centromeric probe. PTEN copy number was also evaluated in a subset of cases using single nucleotide polymorphism (SNP) arrays. In addition, the samples were immunostained with antibodies against p-Akt, p-mTOR, p-70S6, and AR. The PTEN gene was deleted in 77% of cases, with 25% showing homozygous deletions, 18% homozygous and hemizygous deletions, and 34% hemizygous deletions only. In a subset of the study group, SNP array analysis confirmed the FISH findings. PTEN genomic deletion was significantly correlated to the expression of downstream p-Akt (p < 0.0001), AR (p = 0.025), and to cancer-specific mortality (p = 0.039). PTEN deletion is common in HRPC, with bi-allelic loss correlating to disease-specific mortality and associated with Akt and AR deregulation.
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PMID:PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer. 1940 94

Loss of function at the Pten tumor-suppressor locus is a common genetic modification found in human prostate cancer. While recent in vivo and in vitro data support an important role of aberrant ErbB-2 signaling to clinically relevant prostate target genes, such as cyclin D1, the role of Pten in ErbB-2-induced prostate epithelial proliferation is not well understood. In the Pten-deficient prostate cancer cell line, LNCaP, restoration of Pten was able to inhibit ErbB-2- and heregulin-induced cell cycle progression, as well as cyclin D1 protein levels and promoter activity. Previously, we established that probasin-driven ErbB-2 transgenic mice presented with high-grade prostate intraepithelial neoplasia and increased nuclear cyclin D1 levels. We show that mono-allelic loss of pten in the probasin-driven-ErbB-2 model resulted in increased nuclear cyclin D1 and proliferating cell nuclear antigen levels and decreased disease latency compared to either individual genetic model and, unlike the probasin-driven-ErbB-2 mice, progression to adenocarcinoma. Activated 3-phosphoinositide-dependent protein kinase-1 was observed during cancer initiation combined with the activation of p70S6K (phospho-T389) and inactivation of the 4E-binding protein-1 (phosphorylated on T37/46) and was primarily restricted to those cases of prostate cancer that had progressed to adenocarcinoma. Activation of mTOR was not seen. Our data demonstrates that Pten functions downstream of ErbB-2 to restrict prostate epithelial transformation by blocking full activation of the PDK1 signaling cascade.
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PMID:A reduction in Pten tumor suppressor activity promotes ErbB-2-induced mouse prostate adenocarcinoma formation through the activation of signaling cascades downstream of PDK1. 1944 6


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