Transforming growth factor-beta receptor inhibition enhances adenoviral infectability of carcinoma cells via up-regulation of Coxsackie and Adenovirus Receptor in conjunction with reversal of epithelial-mesenchymal transition
Standard
Transforming growth factor-beta receptor inhibition enhances adenoviral infectability of carcinoma cells via up-regulation of Coxsackie and Adenovirus Receptor in conjunction with reversal of epithelial-mesenchymal transition. / Lacher, Markus D; Tiirikainen, Maarit I; Saunier, Elise F; Christian, Christine; Anders, Mario; Oft, Martin; Balmain, Allan; Akhurst, Rosemary J; Korn, Wolfgang Michael.
in: CANCER RES, Jahrgang 66, Nr. 3, 01.02.2006, S. 1648-57.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Transforming growth factor-beta receptor inhibition enhances adenoviral infectability of carcinoma cells via up-regulation of Coxsackie and Adenovirus Receptor in conjunction with reversal of epithelial-mesenchymal transition
AU - Lacher, Markus D
AU - Tiirikainen, Maarit I
AU - Saunier, Elise F
AU - Christian, Christine
AU - Anders, Mario
AU - Oft, Martin
AU - Balmain, Allan
AU - Akhurst, Rosemary J
AU - Korn, Wolfgang Michael
PY - 2006/2/1
Y1 - 2006/2/1
N2 - Expression of the Coxsackie and Adenovirus Receptor (CAR) is frequently reduced in carcinomas, resulting in decreased susceptibility of such tumors to infection with therapeutic adenoviruses. Because CAR participates physiologically in the formation of tight-junction protein complexes, we examined whether molecular mechanisms known to down-regulate cell-cell adhesions cause loss of CAR expression. Transforming growth factor-beta (TGF-beta)-mediated epithelial-mesenchymal transition (EMT) is a phenomenon associated with tumor progression that is characterized by loss of epithelial-type cell-cell adhesion molecules (including E-cadherin and the tight junction protein ZO-1), gain of mesenchymal biochemical markers, such as fibronectin, and acquisition of a spindle cell phenotype. CAR expression is reduced in tumor cells that have undergone EMT in response to TGF-beta. This down-regulation results from repression of CAR gene transcription, whereas altered RNA stability and increased proteasomal protein degradation play no role. Loss of CAR expression in response to TGF-beta is accompanied by reduced susceptibility to adenovirus infection. Indeed, treatment of carcinoma cells with LY2109761, a specific pharmacologic inhibitor of TGF-beta receptor types I and II kinases, resulted in increased CAR RNA and protein levels as well as improved infectability with adenovirus. This was observed in cells induced to undergo EMT by addition of exogenous TGF-beta and in those that were transformed by endogenous autocrine/paracrine TGF-beta. These findings show down-regulation of CAR in the context of EMT and suggest that combination of therapeutic adenoviruses and TGF-beta receptor inhibitors could be an efficient anticancer strategy.
AB - Expression of the Coxsackie and Adenovirus Receptor (CAR) is frequently reduced in carcinomas, resulting in decreased susceptibility of such tumors to infection with therapeutic adenoviruses. Because CAR participates physiologically in the formation of tight-junction protein complexes, we examined whether molecular mechanisms known to down-regulate cell-cell adhesions cause loss of CAR expression. Transforming growth factor-beta (TGF-beta)-mediated epithelial-mesenchymal transition (EMT) is a phenomenon associated with tumor progression that is characterized by loss of epithelial-type cell-cell adhesion molecules (including E-cadherin and the tight junction protein ZO-1), gain of mesenchymal biochemical markers, such as fibronectin, and acquisition of a spindle cell phenotype. CAR expression is reduced in tumor cells that have undergone EMT in response to TGF-beta. This down-regulation results from repression of CAR gene transcription, whereas altered RNA stability and increased proteasomal protein degradation play no role. Loss of CAR expression in response to TGF-beta is accompanied by reduced susceptibility to adenovirus infection. Indeed, treatment of carcinoma cells with LY2109761, a specific pharmacologic inhibitor of TGF-beta receptor types I and II kinases, resulted in increased CAR RNA and protein levels as well as improved infectability with adenovirus. This was observed in cells induced to undergo EMT by addition of exogenous TGF-beta and in those that were transformed by endogenous autocrine/paracrine TGF-beta. These findings show down-regulation of CAR in the context of EMT and suggest that combination of therapeutic adenoviruses and TGF-beta receptor inhibitors could be an efficient anticancer strategy.
KW - Adenoviridae
KW - Animals
KW - Carcinoma
KW - Coxsackie and Adenovirus Receptor-Like Membrane Protein
KW - Cricetinae
KW - Epithelial Cells
KW - Female
KW - Humans
KW - Mammary Neoplasms, Experimental
KW - Mesoderm
KW - Mice
KW - Phosphatidylinositol 3-Kinases
KW - Receptors, Transforming Growth Factor beta
KW - Receptors, Virus
KW - Skin Neoplasms
KW - Transcription, Genetic
KW - Transforming Growth Factor beta
KW - Up-Regulation
U2 - 10.1158/0008-5472.CAN-05-2328
DO - 10.1158/0008-5472.CAN-05-2328
M3 - SCORING: Journal article
C2 - 16452224
VL - 66
SP - 1648
EP - 1657
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 3
ER -