Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tripeptide, tyroservatide (YSV), has been previously shown to have antitumor effects through unknown mechanism. In the current study, we examined whether YSV modulates the protumorigenic PI3K pathway in human BEL-7402 hepatocarcinoma cells. BEL-7402 hepatocarcinoma was transplanted into the subcutaneous tissues of nude mice, and YSV, at varying doses, was administered. RT-PCR and Western blot were used to analyze the expression of PTEN, AKT, p21 and p27. YSV at doses of 80 microg/kg/day, 160 microg/kg/day and 320 microg/kg/day markedly inhibited the growth of human BEL-7402 hepatocarcinoma (p < 0.05). YSV increased mRNA and protein expression of the tumor-suppressor genes, PTEN, p21 and p27, and inhibited the mRNA and protein expression of the oncogene AKT. Furthermore, YSV administration was associated with dephosphorylation of both PTEN (which activates PTEN) and AKT (which inhibits AKT). These results are consistent with the possibility that YSV mediates inhibition of tumor growth through inhibition of the PI3K pathway and suggests that YSV should be explored for use as an antitumor agent for hepatocarcinoma.
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PMID:Expression of PTEN, p27, p21 and AKT mRNA and protein in human BEL-7402 hepatocarcinoma cells in transplanted tumors of nude mice treated with the tripeptide tyroservatide (YSV). 1618 52

The ability of Frzb/secreted Frizzled-related protein 3 (sFRP3) to inhibit Wnt signaling and the localization of Frzb/sFRP3 on chromosome 2q to a region frequently deleted in cancers have led some investigators to hypothesize that Frzb/sFRP3 is a tumor suppressor gene. Here, we examined the biological effects of Frzb/sFRP3 on an androgen-independent prostate cancer cell model. We showed that expression of Frzb/sFRP3 in PC-3 cells resulted in decreased colony formation in soft agar and a dramatic inhibition of tumor growth in a xenograft mouse model. When cellular morphology was examined, PC-3 cells expressing Frzb/sFRP3 exhibited an increase in cell-cell contact formation accompanied by a pronounced induction of epithelial markers E-cadherin and keratin-8 and down-regulation of mesenchymal markers N-cadherin, fibronectin, and vimentin. This phenomenon suggested a reversal of epithelial-to-mesenchymal transition and a less invasive phenotype. Indeed, further in vitro studies with a Matrigel assay showed that Frzb/sFRP3 decreased the invasive capacity of PC-3 cells. These changes in the biology of PC-3 cells are associated with a decrease in the expression and activities of both matrix metalloproteinase (MMP)-2 and MMP-9 as well as decreases in AKT activation, cytosolic beta-catenin levels, T-cell factor transcription activity, and expression of Slug and Twist. In addition, transfection of PC-3 with a dominant-negative low-density lipoprotein receptor-related protein 5 (DN-LRP5) coreceptor showed similar biological effects as Frzb/sFRP3 transfection. Together, these data suggest that Frzb/sFRP3 and DN-LRP5 exhibit antitumor activity through the reversal of epithelial-to-mesenchymal transition and inhibition of MMP activities in a subset of prostate cancer.
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PMID:Expression of Frzb/secreted Frizzled-related protein 3, a secreted Wnt antagonist, in human androgen-independent prostate cancer PC-3 cells suppresses tumor growth and cellular invasiveness. 1626 97

In multiple myeloma (MM), both vascular endothelial (VEGF) and basic fibroblast growth factor (bFGF) promote tumor growth and survival. We have used the novel indolinone BIBF 1000 to study effects of simultaneous inhibition of VEGF, FGF and transforming growth factor-beta on MM cells and their interactions with bone marrow stroma cells (BMSCs). Both, in the absence and presence of myeloma-stroma cell contacts, BIBF 1000 abrogated BMSC-derived secretion of interleukin-6 (IL-6). In addition, BIBF 1000 directly induced apoptosis in t(4;14)-positive cell lines as well as in CD138+ marrow cells from patients with t(4;14) myeloma. To a similar extent, BIBF 1000 induced apoptosis in MM.1S and MM.1R cells carrying the translocation t(14;16). In case of MM.1S and other dexamethasone-sensitive t(14;16) cell lines, BIBF 1000 and dexamethasone had additive proapoptotic effects. Induction of apoptosis by BIBF 1000 was associated with inhibition of the mitogen-activated protein kinases (MAPK) pathway in t(4;14) and inhibition of the phosphatidyl-inositol-3 kinase/AKT pathway in t(14;16) cells. Apoptotic effects did not occur in t(4;14)-or t(14;16)-positive MM cells carrying n- or k-Ras mutations. The data provide the rationale for clinical evaluation of this class of targeted kinase inhibitors in MM with focus on defined cytogenetic subgroups.
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PMID:Targeting receptor kinases by a novel indolinone derivative in multiple myeloma: abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups. 1627 10

While tumors become addicted to oncogenes like Ras, the microenvironment in which tumor cells reside changes during tumorigenesis; the cells are surrounded initially by normal tissue and later by tumor tissue. Hence, we asked if Ras exerts its oncogenic effects through the same set of effectors during different stages of tumorigenesis. We now show in human cells that the Ras effector pathways MAPK, RalGEF, and PI3K are required to initiate tumor growth. Conversely, activation of the PI3K/AKT pathway replaced Ras once tumors formed, although other effectors were still activated independently of Ras, presumably by factors provided upon the establishment of a tumor microenvironment. Thus, as tumorigenesis progresses the addiction of cancers to their initiating oncogene is reduced to, at least in the case of Ras, the PI3K/AKT pathway.
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PMID:Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. 1628 46

The Akt pathway, an important regulator of cell proliferation and survival, is deregulated in many cancers. The pathway has achieved considerable importance due to the development of kinase inhibitors that are able to successfully reduce tumor growth. This study was conducted to determine the status of the Akt pathway in human breast cancers and to study the relationship between the different component proteins. Expression levels of PTEN, phosphorylated forms of the constituent proteins (Akt, FKHR, mTOR, and S6) and cyclin D1 were evaluated by immunohistochemistry, on consecutive sections from a tissue microarray containing 145 invasive breast cancers and 140 pure ductal carcinomas in-situ. Aberrant expression was correlated statistically with tumor characteristics and disease outcome. The Akt pathway was found to be activated early in breast cancer, in the in-situ stage. In all, 33, 15, 32, and 60% of ductal carcinoma in-situ showed overexpression of Akt, FKHR, mTOR, and cyclin D1. PTEN loss did not correlate statistically with expression of AKT or any of the other proteins with the exception of S6, indicating that Akt activation was not a result of PTEN loss. Expression levels of PTEN and S6 were significantly different in in-situ and invasive cancers, indicating association with disease progression. Loss of PTEN was noted in 11% of in-situ as compared to 26% of invasive cancers, while S6 overexpression was seen in 47% in-situ and in 72% invasive cancers. High-grade carcinomas were associated with PTEN loss, while low-grade carcinomas with good prognostic features showed cyclin D1 overexpression and were associated with longer disease free survival. Additionally, cancers with mTOR overexpression showed a three times greater risk for disease recurrence. Overall, a large proportion of in-situ and invasive breast cancers overexpressed cyclinD1 and S6. Our results may have significant implications in the development and application of targeted therapy.
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PMID:The Akt pathway in human breast cancer: a tissue-array-based analysis. 1634 Nov 49

Decreased oxygen causes a rapid inhibition of mRNA translation. An important regulatory mechanism of translational repression under hypoxic conditions involves inhibition of the mammalian target of rapamycin (mTOR). mTOR is a target of the phosphatase and tensin homologue detected on chromosome 10 (PTEN)/phosphatidylinositol 3-kinase/AKT/TSC2 pathway, a pathway that is frequently mutated in human cancers. Although hypoxia has been shown to inhibit mTOR activity, we show here that the hypoxia-induced inhibition of mTOR activity is attenuated in cells lacking TSC2 or PTEN, resulting in a higher translation rate even under hypoxic conditions. Comparison of mTOR inhibition by hypoxia alone or in combination with rapamycin showed that prolonged exposure to hypoxia was required to fully inhibit mTOR activity even in wild-type cells. Increased mTOR activity and protein synthesis did not translate into enhanced cell proliferation rates. However, lack of TSC2 resulted in a survival advantage when cells were exposed to hypoxia. Protection against hypoxia-induced cell death due to TSC2 deficiency is rapamycin-resistant, suggesting that TSC2 affects an apoptotic pathway. Tumors derived from TSC2 wild-type cells exhibited a growth delay compared with TSC2-deficient tumors, indicating that enhanced mTOR activity is advantageous in the initial phase of tumor growth. Therefore, failure to inhibit mTOR under oxygen-limiting conditions can be affected by upstream activating mutations and increases the survival and growth of hypoxic tumor cells.
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PMID:Mutations in the PI3K/PTEN/TSC2 pathway contribute to mammalian target of rapamycin activity and increased translation under hypoxic conditions. 1645 13

We investigated the significance of erythropoietin receptor (EPOR) expression following treatment with recombinant human erythropoietin (rHuEPO; epoetin alpha) and the effect of recombinant epoetins (epoetin alpha, epoetin beta, and darbepoetin alpha) alone or in combination with anticancer therapy on tumor growth in two well-established preclinical models of breast carcinoma (MDA-MB-231 and MCF-7 cell lines). Expression and localization of EPOR under hypoxic and normoxic conditions in MDA-MB-231 and MCF-7 cells were evaluated by immunoblotting, flow cytometry, and immunohistochemistry. EPOR binding was evaluated using [125I]rHuEPO. Proliferation, migration, and signaling in MDA-MB-231 and MCF-7 cells following treatment with rHuEPO were evaluated. Tumor growth was assessed following administration of recombinant epoetins alone and in combination with paclitaxel (anticancer therapy) in orthotopically implanted MDA-MB-231 and MCF-7 breast carcinoma xenograft models in athymic mice. EPOR expression was detected in both tumor cell lines. EPOR localization was found to be exclusively cytosolic and no specific [125I]rHuEPO binding was observed. There was no stimulated migration, proliferation, or activation of mitogen-activated protein kinase and AKT following rHuEPO treatment. In mice, treatment with recombinant epoetins alone and in combination with paclitaxel resulted in equivalent tumor burdens compared with vehicle-treated controls. Results from our study suggest that although EPOR expression was observed in two well-established breast carcinoma cell lines, it was localized to a cytosolic distribution and did not transduce a signaling cascade in tumors that leads to tumor growth. The addition of recombinant epoetins to paclitaxel did not affect the outcome of paclitaxel therapy in breast carcinoma xenograft models. These results show that recombinant epoetins do not evoke a physiologic response on EPOR-bearing tumor cells as assessed by numerous variables, including growth, migration, and cytotoxic challenge in preclinical in vivo tumor models.
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PMID:Recombinant epoetins do not stimulate tumor growth in erythropoietin receptor-positive breast carcinoma models. 1650 8

Vascular endothelial growth factor (VEGF) is a major mediator of pathologic angiogenesis, a process necessary for the formation of new blood vessels to support tumor growth. Historically, VEGF has been thought to signal via receptor tyrosine kinases, which are not typically considered to be G protein dependent. Here, we show that targeted knockdown of the G protein gng2 gene (Ggamma2) blocks the normal angiogenic process in developing zebrafish embryos. Moreover, loss of gng2 function inhibits the ability of VEGF to promote the angiogenic sprouting of blood vessels by attenuating VEGF induced phosphorylation of phospholipase C-gamma1 (PLCgamma1) and serine/threonine kinase (AKT). Collectively, these results demonstrate a novel interaction between Ggamma2- and VEGF-dependent pathways to regulate the angiogenic process in a whole-animal model. Blocking VEGF function using a humanized anti-VEGF antibody has emerged as a promising treatment for colorectal, non-small lung cell, and breast cancers. However, this treatment may cause considerable side effects. Our findings provide a new opportunity for cotargeting G protein- and VEGF-dependent pathways to synergistically block pathologic angiogenesis, which may lead to a safer and more efficacious therapeutic regimen to fight cancer.
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PMID:Zebrafish G protein gamma2 is required for VEGF signaling during angiogenesis. 1653 12

We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro- and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.
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PMID:HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy. 1671 32

Defective apoptosis renders immortalized epithelial cells highly tumorigenic, but how this is impacted by other common tumor mutations is not known. In apoptosis-defective cells, inhibition of autophagy by AKT activation or by allelic disruption of beclin1 confers sensitivity to metabolic stress by inhibiting an autophagy-dependent survival pathway. While autophagy acts to buffer metabolic stress, the combined impairment of apoptosis and autophagy promotes necrotic cell death in vitro and in vivo. Thus, inhibiting autophagy under conditions of nutrient limitation can restore cell death to apoptosis-refractory tumors, but this necrosis is associated with inflammation and accelerated tumor growth. Thus, autophagy may function in tumor suppression by mitigating metabolic stress and, in concert with apoptosis, by preventing death by necrosis.
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PMID:Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. 1684 65


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