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Identification of a GαGβγ, AKT and PKCα signalome associated with invasive growth in two genetic models of human breast cancer cell epithelial-to-mesenchyinal transition

Radia Ouelaa-Benslama, Olivier De Wever UGent, An Hendrix UGent, Michèle Sabbah, Kathleen Lambein UGent, David Land, Grégoire Prévost, Marc Bracke UGent, Mien-Chie Hung and Annette K Larsen, et al. (2012) INTERNATIONAL JOURNAL OF ONCOLOGY. 41(1). p.189-200
abstract
The epithelial-to-mesenchymal transition (EMT) confers an aggressive subtype associated with chemotherapy resistance in epithelial cancers. However, the mechanisms underlying the EMT and its associated signaling dysfunctions are still poorly understood. In two genetic models of MCF-7 breast cancer cells induced to EMT by WISP-2 silencing and Snail transformation, we investigated the status of several signaling elements downstream of G-protein receptors (GPR) and their functional roles in the invasive growth potential. We report that the E-cadherin repressors Slug, Zeb1/2 and Twist are overexpressed in these EMT cells characterized by a triple negative phenotype (loss of estrogen ER alpha and progesterone PRA/PRB receptors, no HER2 amplification), combined with loss of the alternative GPR30 estrogen receptor and induction of the invasive growth in collagen type I gels. Ectopic Snail expression suppressed WISP-2 transcripts and downregulated WISP-2 gene promoter expression in transfected cells. Accordingly, WISP-2 transcripts and Wisp-2 protein were depleted in these two convergent models of BC cell EMT. The EMT caused dominance of several proinvasive pathways downstream of GPR, including G alpha G beta gamma subunits, PKC alpha, AKT and c-Jun induction, constitutive activation of the actin-remodeling GTPase Rac1, coupled with growth responses (more cells at S and G2/M phases of the cell cycle), in line with inhibition of the p27(kip1)/cyclin-dependent kinase CDK3 cascade. RNA interference or selective inhibitors targeting G alpha G beta gamma subunits (BIM-46187, gallein), PKC alpha (Go6976, MT477, sh-RNAs) and PI3K-AKT (wortmannin:, alleviated the invasive phenotype. In contrast, MCF-7 cells in EMT showed signaling independence to inhibitors of HER family tyrosine kinases and the mitogen- and stress-activated protein kinases. Our study suggests that the signaling protagonists G alpha G beta gamma, PKC alpha and PI3K-AKT are promising candidates as predictive molecular biomarkers and therapeutic targets in the management of clinical BC in EMT.
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author
organization
alternative title
Identification of a G alpha G beta gamma, AKT and PKC alpha signalome associated with invasive growth in two genetic models of human breast cancer cell epithelial-to-mesenchyinal transition
year
type
journalArticle (original)
publication status
published
subject
keyword
WISP-2, Snail, Rac1 GTPase, GPR30, short-herpin RNAs, p27, protein kinase C-alpha, targeted-therapy, PROTEIN-COUPLED RECEPTORS, prognosis, HER family, DOWN-REGULATION, ESTROGEN-RECEPTOR, METASTASIS, DRUG DISCOVERY, EXPRESSION, ACTIVATION, P27(KIP1), PATHWAY, CYCLE
journal title
INTERNATIONAL JOURNAL OF ONCOLOGY
Int. J. Oncol.
volume
41
issue
1
pages
189 - 200
Web of Science type
Article
Web of Science id
000304578800024
JCR category
ONCOLOGY
JCR impact factor
2.657 (2012)
JCR rank
95/196 (2012)
JCR quartile
2 (2012)
ISSN
1019-6439
DOI
10.3892/ijo.2012.1457
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2941298
handle
http://hdl.handle.net/1854/LU-2941298
date created
2012-06-28 12:52:20
date last changed
2012-07-10 13:47:57
@article{2941298,
  abstract     = {The epithelial-to-mesenchymal transition (EMT) confers an aggressive subtype associated with chemotherapy resistance in epithelial cancers. However, the mechanisms underlying the EMT and its associated signaling dysfunctions are still poorly understood. In two genetic models of MCF-7 breast cancer cells induced to EMT by WISP-2 silencing and Snail transformation, we investigated the status of several signaling elements downstream of G-protein receptors (GPR) and their functional roles in the invasive growth potential. We report that the E-cadherin repressors Slug, Zeb1/2 and Twist are overexpressed in these EMT cells characterized by a triple negative phenotype (loss of estrogen ER alpha and progesterone PRA/PRB receptors, no HER2 amplification), combined with loss of the alternative GPR30 estrogen receptor and induction of the invasive growth in collagen type I gels. Ectopic Snail expression suppressed WISP-2 transcripts and downregulated WISP-2 gene promoter expression in transfected cells. Accordingly, WISP-2 transcripts and Wisp-2 protein were depleted in these two convergent models of BC cell EMT. The EMT caused dominance of several proinvasive pathways downstream of GPR, including G alpha G beta gamma subunits, PKC alpha, AKT and c-Jun induction, constitutive activation of the actin-remodeling GTPase Rac1, coupled with growth responses (more cells at S and G2/M phases of the cell cycle), in line with inhibition of the p27(kip1)/cyclin-dependent kinase CDK3 cascade. RNA interference or selective inhibitors targeting G alpha G beta gamma subunits (BIM-46187, gallein), PKC alpha (Go6976, MT477, sh-RNAs) and PI3K-AKT (wortmannin:, alleviated the invasive phenotype. In contrast, MCF-7 cells in EMT showed signaling independence to inhibitors of HER family tyrosine kinases and the mitogen- and stress-activated protein kinases. Our study suggests that the signaling protagonists G alpha G beta gamma, PKC alpha and PI3K-AKT are promising candidates as predictive molecular biomarkers and therapeutic targets in the management of clinical BC in EMT.},
  author       = {Ouelaa-Benslama, Radia and De Wever, Olivier and Hendrix, An and Sabbah, Mich{\`e}le and Lambein, Kathleen and Land, David and Pr{\'e}vost, Gr{\'e}goire and Bracke, Marc and Hung, Mien-Chie and Larsen, Annette K and Emami, Shahin and Gespach, Christian},
  issn         = {1019-6439},
  journal      = {INTERNATIONAL JOURNAL OF ONCOLOGY},
  keyword      = {WISP-2,Snail,Rac1 GTPase,GPR30,short-herpin RNAs,p27,protein kinase C-alpha,targeted-therapy,PROTEIN-COUPLED RECEPTORS,prognosis,HER family,DOWN-REGULATION,ESTROGEN-RECEPTOR,METASTASIS,DRUG DISCOVERY,EXPRESSION,ACTIVATION,P27(KIP1),PATHWAY,CYCLE},
  language     = {eng},
  number       = {1},
  pages        = {189--200},
  title        = {Identification of a G\ensuremath{\alpha}G\ensuremath{\beta}\ensuremath{\gamma}, AKT and PKC\ensuremath{\alpha} signalome associated with invasive growth in two genetic models of human breast cancer cell epithelial-to-mesenchyinal transition},
  url          = {http://dx.doi.org/10.3892/ijo.2012.1457},
  volume       = {41},
  year         = {2012},
}

Chicago
Ouelaa-Benslama, Radia, Olivier De Wever, An Hendrix, Michèle Sabbah, Kathleen Lambein, David Land, Grégoire Prévost, et al. 2012. “Identification of a GαGβγ, AKT and PKCα Signalome Associated with Invasive Growth in Two Genetic Models of Human Breast Cancer Cell Epithelial-to-mesenchyinal Transition.” International Journal of Oncology 41 (1): 189–200.
APA
Ouelaa-Benslama, R., De Wever, O., Hendrix, A., Sabbah, M., Lambein, K., Land, D., Prévost, G., et al. (2012). Identification of a GαGβγ, AKT and PKCα signalome associated with invasive growth in two genetic models of human breast cancer cell epithelial-to-mesenchyinal transition. INTERNATIONAL JOURNAL OF ONCOLOGY, 41(1), 189–200.
Vancouver
1.
Ouelaa-Benslama R, De Wever O, Hendrix A, Sabbah M, Lambein K, Land D, et al. Identification of a GαGβγ, AKT and PKCα signalome associated with invasive growth in two genetic models of human breast cancer cell epithelial-to-mesenchyinal transition. INTERNATIONAL JOURNAL OF ONCOLOGY. 2012;41(1):189–200.
MLA
Ouelaa-Benslama, Radia, Olivier De Wever, An Hendrix, et al. “Identification of a GαGβγ, AKT and PKCα Signalome Associated with Invasive Growth in Two Genetic Models of Human Breast Cancer Cell Epithelial-to-mesenchyinal Transition.” INTERNATIONAL JOURNAL OF ONCOLOGY 41.1 (2012): 189–200. Print.