TRPM4 regulates Akt/GSK3-b activity and enhances b-catenin signaling and cell proliferation in prostate cancer cells
Author
dc.contributor.author
Sagredo, A.
Author
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Sagredo, Eduardo A.
Author
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Cappelli, Claudio
Author
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Baez, Pablo
Author
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Andaur, Rodrigo E.
Author
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Blanco, Constanza
Author
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Tapia, Julio C.
Author
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Echeverría, César
Author
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Cerda, Oscar
Author
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Stutzin Schottlander, Andrés
Author
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Simon, Felipe
Author
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Marcelain Cubillos, Katherine
Author
dc.contributor.author
Armisen Yáñez, Ricardo
Admission date
dc.date.accessioned
2018-07-26T15:56:14Z
Available date
dc.date.available
2018-07-26T15:56:14Z
Publication date
dc.date.issued
2018
Cita de ítem
dc.identifier.citation
Molecular Oncology 12 (2018) 151–165
es_ES
Identifier
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18780261
Identifier
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15747891
Identifier
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10.1002/1878-0261.12100
Identifier
dc.identifier.uri
https://repositorio.uchile.cl/handle/2250/150325
Abstract
dc.description.abstract
Increased expression of the TRPM4 channel has been reported to be associated
with the progression of prostate cancer. However, the molecular
mechanism underlying its effect remains unknown. This work found that
decreasing TRPM4 levels leads to the reduced proliferation of PC3 cells.
This effect was associated with a decrease in total b-catenin protein levels
and its nuclear localization, and a significant reduction in Tcf/Lef transcriptional
activity. Moreover, TRPM4 silencing increases the Ser33/Ser37/
Thr41 b-catenin phosphorylated population and reduces the phosphorylation
of GSK-3b at Ser9, suggesting an increase in b-catenin degradation as
the underlying mechanism. Conversely, TRPM4 overexpression in LNCaP
cells increases the Ser9 inhibitory phosphorylation of GSK-3b and the total
levels of b-catenin and its nonphosphorylated form. Finally, PC3 cells with
reduced levels of TRPM4 showed a decrease in basal and stimulated phosphoactivation
of Akt1, which is likely responsible for the decrease in GSK3b
activity in these cells. Our results also suggest that the effect of TRPM4
on Akt1 is probably mediated by an alteration in the calcium/calmodulinEGFR
axis, linking TRPM4 activity with the observed effects in b-cateninrelated
signaling pathways. These results suggest a role for TRPM4
channels in b-catenin oncogene signaling and underlying mechanisms, highlighting
this ion channel as a new potential target for future therapies in
prostate cancer.