Distinct functional roles of Akt isoforms for proliferation, survival, migration and EGF-mediated signalling in lung cancer derived disseminated tumor cells
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Distinct functional roles of Akt isoforms for proliferation, survival, migration and EGF-mediated signalling in lung cancer derived disseminated tumor cells. / Grabinski, Nicole; Bartkowiak, Kai; Grupp, Katharina; Brandt, Burkhard; Pantel, Klaus; Jücker, Manfred.
In: CELL SIGNAL, Vol. 23, No. 12, 12, 12.2011, p. 1952-1960.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Distinct functional roles of Akt isoforms for proliferation, survival, migration and EGF-mediated signalling in lung cancer derived disseminated tumor cells
AU - Grabinski, Nicole
AU - Bartkowiak, Kai
AU - Grupp, Katharina
AU - Brandt, Burkhard
AU - Pantel, Klaus
AU - Jücker, Manfred
N1 - Copyright © 2011 Elsevier Inc. All rights reserved.
PY - 2011/12
Y1 - 2011/12
N2 - Single disseminated tumor cells (DTC) can be detected in the bone marrow (BM) from 20% to 60% of patients with various tumors including non-small cell lung cancer (NSCLC). Detection of DTC in the BM of NSCLC patients is associated with poor prognosis and may be responsible for metastatic relapse. However, the functional properties of DTC are widely unknown. Here, we performed the first functional analysis of DTC focusing on the activation of the PI3K/Akt signalling pathway and the functional roles of Akt isoforms. In vitro kinase assays revealed a high activity of Akt3 in NSCLC-derived DTC. Proliferation and survival of DTC was reduced by depletion of Akt3 and to a lesser extend by Akt1, but not after depletion of Akt2. The major effect of Akt3 on the proliferation of DTC was associated with an Akt3-mediated regulation of both, cyclin D1 and cyclin D3, whereas Akt1 regulated the expression of cyclin D1 only. In contrast all three Akt isoforms, especially Akt2, were involved in the regulation of migration. Analysis of signalling events downstream of distinct Akt isoforms revealed that expression levels of urokinase-type plasminogen activator and its receptor were decreased after knockdown of Akt1 and Akt3. In addition, EGF-stimulated proliferative and anti-apoptotic signals are mediated by Akt1 and Akt3 in DTC. Finally, by immunofluorescence staining of primary DTC from BM samples of lung cancer patients, pAkt(S473) and Akt3 positive DTC were detected in vivo. Our data demonstrate that Akt1 and notably Akt3 regulate proliferation, survival, migration and EGF-mediated signal transduction in NSCLC-derived DTC.
AB - Single disseminated tumor cells (DTC) can be detected in the bone marrow (BM) from 20% to 60% of patients with various tumors including non-small cell lung cancer (NSCLC). Detection of DTC in the BM of NSCLC patients is associated with poor prognosis and may be responsible for metastatic relapse. However, the functional properties of DTC are widely unknown. Here, we performed the first functional analysis of DTC focusing on the activation of the PI3K/Akt signalling pathway and the functional roles of Akt isoforms. In vitro kinase assays revealed a high activity of Akt3 in NSCLC-derived DTC. Proliferation and survival of DTC was reduced by depletion of Akt3 and to a lesser extend by Akt1, but not after depletion of Akt2. The major effect of Akt3 on the proliferation of DTC was associated with an Akt3-mediated regulation of both, cyclin D1 and cyclin D3, whereas Akt1 regulated the expression of cyclin D1 only. In contrast all three Akt isoforms, especially Akt2, were involved in the regulation of migration. Analysis of signalling events downstream of distinct Akt isoforms revealed that expression levels of urokinase-type plasminogen activator and its receptor were decreased after knockdown of Akt1 and Akt3. In addition, EGF-stimulated proliferative and anti-apoptotic signals are mediated by Akt1 and Akt3 in DTC. Finally, by immunofluorescence staining of primary DTC from BM samples of lung cancer patients, pAkt(S473) and Akt3 positive DTC were detected in vivo. Our data demonstrate that Akt1 and notably Akt3 regulate proliferation, survival, migration and EGF-mediated signal transduction in NSCLC-derived DTC.
KW - Humans
KW - Female
KW - Cell Line, Tumor
KW - Gene Expression
KW - Gene Knockdown Techniques
KW - Phosphorylation
KW - Cell Proliferation
KW - Signal Transduction
KW - Bone Marrow Neoplasms/metabolism/physiopathology/secondary
KW - Breast Neoplasms/pathology
KW - Carcinoma, Non-Small-Cell Lung/metabolism/physiopathology/secondary
KW - Cell Movement
KW - Cell Survival
KW - Enzyme Assays
KW - Epidermal Growth Factor/pharmacology/physiology
KW - Glycogen Synthase Kinase 3/metabolism
KW - Isoenzymes/metabolism
KW - Lung Neoplasms/pathology
KW - Proto-Oncogene Proteins c-akt/genetics/metabolism
KW - RNA Interference
KW - Receptor, Epidermal Growth Factor/metabolism
KW - Receptor, erbB-2/metabolism
KW - Receptor, erbB-3/metabolism
KW - Receptors, Urokinase Plasminogen Activator/genetics/metabolism
KW - Urokinase-Type Plasminogen Activator/genetics/metabolism
KW - Humans
KW - Female
KW - Cell Line, Tumor
KW - Gene Expression
KW - Gene Knockdown Techniques
KW - Phosphorylation
KW - Cell Proliferation
KW - Signal Transduction
KW - Bone Marrow Neoplasms/metabolism/physiopathology/secondary
KW - Breast Neoplasms/pathology
KW - Carcinoma, Non-Small-Cell Lung/metabolism/physiopathology/secondary
KW - Cell Movement
KW - Cell Survival
KW - Enzyme Assays
KW - Epidermal Growth Factor/pharmacology/physiology
KW - Glycogen Synthase Kinase 3/metabolism
KW - Isoenzymes/metabolism
KW - Lung Neoplasms/pathology
KW - Proto-Oncogene Proteins c-akt/genetics/metabolism
KW - RNA Interference
KW - Receptor, Epidermal Growth Factor/metabolism
KW - Receptor, erbB-2/metabolism
KW - Receptor, erbB-3/metabolism
KW - Receptors, Urokinase Plasminogen Activator/genetics/metabolism
KW - Urokinase-Type Plasminogen Activator/genetics/metabolism
U2 - 10.1016/j.cellsig.2011.07.003
DO - 10.1016/j.cellsig.2011.07.003
M3 - SCORING: Journal article
C2 - 21777670
VL - 23
SP - 1952
EP - 1960
JO - CELL SIGNAL
JF - CELL SIGNAL
SN - 0898-6568
IS - 12
M1 - 12
ER -