Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer

Yuan, Zeng; Sun, Mei; Feldman, Richard I.; Wang, Gen; Ma, Xiaojie; Jiang, Chen Chen; Coppola, Domenico; Nicosia, Santo V.; Cheng, Jin Q.

doi:10.1038/sj.onc.1203598

Cited by 333 publications

(258 citation statements)

References 38 publications

(39 reference statements)

Supporting

Mentioning

247

Contrasting

Unclassified

Order By: Relevance

“…This is consistent with most other reports for malignant cells in which the reported subcellular localisation of pAKT staining is cytoplasmic (Gupta et al, 2002;Perez-Tenorio and Stal, 2002) and nuclear (Dhawan et al, 2002;Itoh et al, 2002). Membrane staining is commonly observed in nontransformed cells and has also been reported in malignant cells though usually as a component of cytoplasmic staining (Yuan et al, 2000).…”

Section: Incidence Of Activated Akt In Pancreatic Adenocarcinoma Tumourssupporting

confidence: 92%

Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

et al. 2003

View full text Add to dashboard Cite

When activated, the serine/threonine kinase AKT mediates an antiapoptotic signal implicated in chemoresistance of various cancers. The mechanism(s) of AKT activation are unknown, though overexpression of HER-2/neu has been implicated in breast cancer. Therefore, we determined the incidence of activated AKT in human pancreatic cancer, whether HER-2/neu is involved in AKT activation, and if AKT activation is associated with biologic behaviour. HER-2/neu expression and AKT activation were examined in seven pancreatic cancer cell lines by Western blotting. The in vitro effect of HER-2/neu inhibition on AKT activation was similarly determined. Finally, 78 pancreatic cancer specimens were examined for AKT activation and HER-2/neu overexpression, and correlated with the clinical prognostic variable of histologic grade. HER-2/neu was overexpressed in two of seven cell lines; these two cell lines demonstrated the highest level of AKT activation. Inhibition of HER-2/neu reduced AKT activation in vitro. AKT was activated in 46 out of 78 (59%) of the pancreatic cancers; HER-2/neu overexpression correlated with AKT activation (P ¼ 0.015). Furthermore, AKT activation was correlated with higher histologic tumour grade (P ¼ 0.047). Thus, it is concluded that AKT is frequently activated in pancreatic cancer; this antiapoptotic signal may be mediated by HER-2/neu overexpression. AKT activation is associated with tumour grade, an important prognostic factor.

show abstract

Section: Incidence Of Activated Akt In Pancreatic Adenocarcinoma Tumourssupporting

confidence: 92%

Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

et al. 2003

View full text Add to dashboard Cite

show abstract

“…In Vitro Protein Kinase Assay-Protein kinase assays were performed as previously described (26,27). Briefly, reactions were carried out in the presence of 10 Ci of [␥-32 P] ATP (PerkinElmer Life Sciences) and 3 M cold ATP in 30 l of buffer containing 20 mM Hepes (pH 7.4), 10 mM MgCl 2 , 10 mM MnCl 2 , and 1 mM dithiothreitol.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of JNK by Cellular Stress- and Tumor Necrosis Factor α-induced AKT2 through Activation of the NFκB Pathway in Human Epithelial Cells

Yuan¹,

Feldman²,

Sun³

et al. 2002

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Previous studies have demonstrated that AKT1 and AKT3 are activated by heat shock and oxidative stress via both phosphatidylinositol 3-kinase-dependent and -independent pathways. However, the activation and role of AKT2 in the stress response have not been fully elucidated. In this study, we show that AKT2 in epithelial cells is activated by UV-C irradiation, heat shock, and hyperosmolarity as well as by tumor necrosis factor ␣ (TNF␣) through a phosphatidylinositol 3-kinase-dependent pathway. The activation of AKT2 inhibits UVand TNF␣-induced c-Jun N-terminal kinase (JNK) and p38 activities that have been shown to be required for stress-and TNF␣-induced programmed cell death. Moreover, AKT2 interacts with and phosphorylates I B kinase ␣. The phosphorylation of I B kinase ␣ and activation of NF B mediates AKT2 inhibition of JNK but not p38. Furthermore, phosphatidylinositol 3-kinase inhibitor or dominant negative AKT2 significantly enhances UV-and TNF␣-induced apoptosis, whereas expression of constitutively active AKT2 inhibits programmed cell death in response to UV and TNF␣ stimulation with an accompanying decreased JNK and p38 activity. These results indicate that activated AKT2 protects epithelial cells from stress-and TNF␣-induced apoptosis by inhibition of stress kinases and provide the first evidence that AKT inhibits stress kinase JNK through activation of the NF B pathway.

show abstract

“…Phosphorylation of S473 on Akt is coincident with Akt activation in vivo and in vitro and has been used as a marker for PI3K activity by using phospho-specific antibodies [29]. Phosphorylation of Akt was most prominent in WT cells in response to sulfatide but detectable in the L-sel -/-cells (Fig.…”

Section: Sulfatide-induced Tyrosine Phosphorylation Is Essential For mentioning

confidence: 98%

Up‐regulation of leukocyte CXCR4 expression by sulfatide: An L‐selectin‐dependent pathway on CD4⁺ T cells

et al. 2007

View full text Add to dashboard Cite

CXCR4 plays significant roles in immune and inflammatory responses and is important for selective recruitment of leukocytes. We previously showed that CXCR4 surface expression of human lymphocytes was affected by sulfatide, an in vivo ligand for L-selectin. Increased CXCR4 expression was shown to promote biologically relevant functions such as integrin-dependent adhesion and transmigration. Here, we show that sulfatide-induced CXCR4 up-regulation also occurs on other leukocyte subsets in humans and mice. B cells and CD4 + CD25 + T cells had the highest CXCR4 up-regulation after sulfatide stimulation. Transfection of L-selectin was sufficient for K562 cells to acquire sulfatide-induced CXCR4 up-regulation, while analysis of L-selectin knockout mice revealed that this response was critically L-selectin dependent only for CD4 + T cells, suggesting an alternative pathway in CD8 + T cells and B cells. Sulfatide triggered several intracellular signaling events in CD4 + T cells, but only tyrosine kinase activation, including members of the Src family, were essential for L-selectin to CXCR4 signaling. CXCR4 up-regulation was rapid, enhanced CXCL12-induced signaling and increased chemotaxis toward CXCL12, and therefore has potentially important roles in vivo. Thus, the response to CXCL12 depends in part on tissue expression of sulfatide and, specifically in CD4 + T cells, also depends on the surface level of L-selectin.

show abstract

Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer

Cited by 333 publications

References 38 publications

Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

Inhibition of JNK by Cellular Stress- and Tumor Necrosis Factor α-induced AKT2 through Activation of the NFκB Pathway in Human Epithelial Cells

Up‐regulation of leukocyte CXCR4 expression by sulfatide: An L‐selectin‐dependent pathway on CD4⁺ T cells

Contact Info

Product

Resources

About

Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer

Cited by 333 publications

References 38 publications

Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

Inhibition of JNK by Cellular Stress- and Tumor Necrosis Factor α-induced AKT2 through Activation of the NFκB Pathway in Human Epithelial Cells

Up‐regulation of leukocyte CXCR4 expression by sulfatide: An L‐selectin‐dependent pathway on CD4+ T cells

Contact Info

Product

Resources

About

Up‐regulation of leukocyte CXCR4 expression by sulfatide: An L‐selectin‐dependent pathway on CD4⁺ T cells