R pathway in pancreatic cells. Cyclooxygenase-2 (COX-2) is expressed at high levels in some primary endometrial tumors and is associated with an aggressive phenotype [370]. Akt is elevated and PTEN is often mutated in these cancers which can result in Akt activation. NF-kappaB activation has been shown to have Ensartinib biological activity oncogenic effects important in the control of apoptosis, cell cycle, differentiation, cell migration and inflammation [371-383]. Akt may exert its effects through the NF-kappaB pathway and COX2 is the regulator of this pathway. Akt regulates COX2 gene and protein expression in endometrial cancers. This study was undertaken to examine the involvement of Akt in the regulation of NF- kappaB and COX-2 [370]. The expression of both I-kappaB and phosphorylated I-kappaB were increased in the cells containing mutant PTEN genes. In contrast, there was no difference in NFkappaB protein abundance between the cell lines, which differed in PTEN gene status. I-kappaB phosphorylation by the PI3K pathway was inhibited by the PI3K inhibitors Wortmannin and LY294002. There was less NF-kappaB nuclear activity, less COX-2 expression and more apoptosis after inhibition of the PI3K pathway. Dominant negative (DN) Akt blocked I-kappaB phosphorylation and decreased COX-2 expression. In contrast, introduction of constitutively-active Akt induced I-kappaB phosphorylation and up-regulated COX-2 expression. When PTEN is mutated, Akt signals via the NFkappaB/I-kappaB pathway to induce COX-2 expression in endometrial cancer cells. COX-2 can inhibit apoptosis, increase angiogenesis, and promote invasiveness. COX2 also promotes inflammation/immunosuppression and conversion of procarcinogens into carcinogens that contribute to tumorigenesis and a malignant phenotype. This study demonstrated that Akt signals via the NFkappaB/I-kappaB pathway to induce COX2 gene and protein expression in endometrial cancer [370]. Elevated Akt activity can also result in increased phosphorylation of mTOR. mTOR was found to be phosphorylated in AML blasts, along with its two downstream substrates, p70S6K and 4EBP-1, in a PI3K/ Akt-dependent fashion [384]. Nevertheless, others failed to detect any relationship between PI3K/Akt signalling upregulation and p70S6K phosphorylation in AML primary cells [385]. This might occur via the Ras/Oncotarget 2012; 3: 954-Raf/MEK/ERK pathway activating mTOR via ERK phosphorylation [385]. The Ras/Raf/MEK/ERK pathway is frequently activated in AML [386-388]. Akt is activated in HCC, which results in enhanced resistance to apoptosis through multiple mechanisms [389-392]. As an example, activation of the Akt pathway suppresses transforming growth factor-beta (TGFbeta) induced apoptosis and growth-inhibitory activity of CCAAT/enhancer binding protein alpha (CEBPalpha). Activation of Akt is a risk factor for early disease recurrence and poor prognosis in patients with HCC [390]. purchase PG-1016548 Several mechanisms may be responsible for the activation of Akt. The high frequency of PIK3CA mutations and/or its upregulation in patients with shorter survival might be responsible for the Akt hyperactivation found in HCC with poor prognosis [335-341]. Selective epigenetic silencing of multiple inhibitors of the Ras pathway seems also to be responsible for the activation of Akt found in HCC [327]. Moreover, impaired expression of PTEN is involved in the regulation of Akt activity. Activation of Akt signaling and reduced expression of PTEN has been reported in 40 ?0 of human HCC.R pathway in pancreatic cells. Cyclooxygenase-2 (COX-2) is expressed at high levels in some primary endometrial tumors and is associated with an aggressive phenotype [370]. Akt is elevated and PTEN is often mutated in these cancers which can result in Akt activation. NF-kappaB activation has been shown to have oncogenic effects important in the control of apoptosis, cell cycle, differentiation, cell migration and inflammation [371-383]. Akt may exert its effects through the NF-kappaB pathway and COX2 is the regulator of this pathway. Akt regulates COX2 gene and protein expression in endometrial cancers. This study was undertaken to examine the involvement of Akt in the regulation of NF- kappaB and COX-2 [370]. The expression of both I-kappaB and phosphorylated I-kappaB were increased in the cells containing mutant PTEN genes. In contrast, there was no difference in NFkappaB protein abundance between the cell lines, which differed in PTEN gene status. I-kappaB phosphorylation by the PI3K pathway was inhibited by the PI3K inhibitors Wortmannin and LY294002. There was less NF-kappaB nuclear activity, less COX-2 expression and more apoptosis after inhibition of the PI3K pathway. Dominant negative (DN) Akt blocked I-kappaB phosphorylation and decreased COX-2 expression. In contrast, introduction of constitutively-active Akt induced I-kappaB phosphorylation and up-regulated COX-2 expression. When PTEN is mutated, Akt signals via the NFkappaB/I-kappaB pathway to induce COX-2 expression in endometrial cancer cells. COX-2 can inhibit apoptosis, increase angiogenesis, and promote invasiveness. COX2 also promotes inflammation/immunosuppression and conversion of procarcinogens into carcinogens that contribute to tumorigenesis and a malignant phenotype. This study demonstrated that Akt signals via the NFkappaB/I-kappaB pathway to induce COX2 gene and protein expression in endometrial cancer [370]. Elevated Akt activity can also result in increased phosphorylation of mTOR. mTOR was found to be phosphorylated in AML blasts, along with its two downstream substrates, p70S6K and 4EBP-1, in a PI3K/ Akt-dependent fashion [384]. Nevertheless, others failed to detect any relationship between PI3K/Akt signalling upregulation and p70S6K phosphorylation in AML primary cells [385]. This might occur via the Ras/Oncotarget 2012; 3: 954-Raf/MEK/ERK pathway activating mTOR via ERK phosphorylation [385]. The Ras/Raf/MEK/ERK pathway is frequently activated in AML [386-388]. Akt is activated in HCC, which results in enhanced resistance to apoptosis through multiple mechanisms [389-392]. As an example, activation of the Akt pathway suppresses transforming growth factor-beta (TGFbeta) induced apoptosis and growth-inhibitory activity of CCAAT/enhancer binding protein alpha (CEBPalpha). Activation of Akt is a risk factor for early disease recurrence and poor prognosis in patients with HCC [390]. Several mechanisms may be responsible for the activation of Akt. The high frequency of PIK3CA mutations and/or its upregulation in patients with shorter survival might be responsible for the Akt hyperactivation found in HCC with poor prognosis [335-341]. Selective epigenetic silencing of multiple inhibitors of the Ras pathway seems also to be responsible for the activation of Akt found in HCC [327]. Moreover, impaired expression of PTEN is involved in the regulation of Akt activity. Activation of Akt signaling and reduced expression of PTEN has been reported in 40 ?0 of human HCC.
