Phosphorylation of Akt/PKB is required for suppression of cancer cell apoptosis and tumor progression in human colorectal carcinoma

Itoh, Nanami; Semba, Shuho; Ito, Masafumi; Takeda, Hiroaki; Kawata, Sumio; Yamakawa, Mitsunori

doi:10.1002/cncr.10591

Cited by 213 publications

(173 citation statements)

References 28 publications

(41 reference statements)

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“…The typical pattern of pAKT staining we observed included both cytoplasmic and nuclear immunostaining. 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: 91%

“…In vitro data have coupled AKT to the survival pathway of the transcription factor NF-kB. This is particularly interesting given three observations: (1) the frequent constitutive activation of NF-kB in various cancers including pancreatic tumour specimens (Wang et al, 1999), (2) the nuclear immunostaining pattern of pAKT frequently observed in various tumours (Dhawan et al, 2002;Itoh et al, 2002;Perez-Tenorio and Stal, 2002), and (3) the correlation of pAKT immunostaining and nuclear localisation of the p65 subunit of NF-kB in melanoma specimens (Dhawan et al, 2002). We have previously shown in the MIA-PaCa-2 cells that AKT is coupled to NF-kB activation and alters levels of various members of the apoptosis-regulating BCL-2 family (Fahy et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Constitutive activation of AKT provides a potent antiapoptotic signal in cancer cells conferring chemo-and radioresistance (Brognard et al, 2001;West et al, 2002). To date, there have been a few studies on the incidence of AKT activation in various tumours using archived pathologic specimens (Dhawan et al, 2002;Gupta et al, 2002;Itoh et al, 2002;Malik et al, 2002;Perez-Tenorio and Stal, 2002). While these reports correlate AKT activation with some biologic property of the tumour, none has examined potential upstream activating mechanisms.…”

mentioning

confidence: 99%

“…While these reports correlate AKT activation with some biologic property of the tumour, none has examined potential upstream activating mechanisms. In prostate cancer, the AKT activation occurred in 33 out of 125 specimens and was more frequent in higher Gleason grade cancers (Malik et al, 2002); in colon cancer, the AKT activation was observed in 30 out of 65 tumours and associated with advanced clinicopathologic stage (Itoh et al, 2002); in breast cancer, the AKT activation was frequently observed (50 out of 93) and predicted a worse prognosis in endocrine treated patients (Perez-Tenorio and Stal, 2002); in melanoma, the AKT activation was observed in eight out of 12 specimens and the incidence of AKT activation was more common than in precursor lesions (Dhawan et al, 2002); and in head and neck squamous cell carcinoma, the AKT activation was observed in 25 out of 38 (66%) specimens and correlated with local recurrence (Gupta et al, 2002).…”

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confidence: 99%

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

et al. 2003

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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.

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Section: Incidence Of Activated Akt In Pancreatic Adenocarcinoma Tumourssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2003

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“…Activated MAPK was also reported in glial tumours and in a group of oligodendrogliomas, an increase in the proportions of cells expressing activated MAPK corresponded with malignant progression (Mandell et al, 1998). Sivaraman et al (Itoh et al, 2002) provided the first demonstration of MAPK activation in human breast cancer tissues, comparing primary breast cancer with benign lesions using substrate-based MAPK enzyme assays and immunoblotting. They found significantly less MAPK activity to be in benign breast tissues compared with invasive breast cancers.…”

Section: Discussionmentioning

confidence: 99%

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

et al. 2004

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One of the major targets for breast cancer therapy is the epidermal growth factor receptor (EGFR) and related receptors, which signal via different signal transduction pathways including the mitogen-activated protein kinase (MAPK) pathway. This study determined whether there is a correlation between EGFR/HER2 status and MAPK (ERK1/2) phosphorylation in breast cancer cells, and how this affects the response to an inhibitor of the receptors. Expression of EGFR, HER2 and phosphorylated ERK1/2 were measured by immunoblotting in a panel of breast cancer cell lines. Several lines expressed high levels of pERK1/2, with no obvious correlation with the level of EGFR/HER2. The EGFR tyrosine kinase inhibitor PKI166 inhibited growth and induced apoptosis in some cells with high levels of growth factor receptors (MDA-MB-468, SUM149, SKBR3), but was less effective in cells that also had high basal ERK1/2 activity (MDA-MB-231). The combination of an inhibitor of MAPK signalling (U0126) and PKI166 produced significantly more inhibition and apoptosis than either agent alone. This suggests that constitutive activation of the MAPK pathway may bypass inhibition of EGFR/HER2 tyrosine kinases, and lead to insensitivity to agents targeting the receptors. However, inhibiting both EGFR/ HER2 and MAPK signalling can result in significant growth inhibition and apoptosis of EGFR-expressing breast cancer cells.

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