Caveolin-1 Dephosphorylation-dependent Upregulation of Desmosomal Proteins by Kv11.1 Activator NS1643
Jaden Blankenship
Illinois Math and Science Academy, Aurora, IL, USA
Publication date: December 25, 2024
Illinois Math and Science Academy, Aurora, IL, USA
Publication date: December 25, 2024
DOI: http://doi.org/10.34614/JIYRC202429
ABSTRACT
One of the primary objectives of cancer therapy is the prevention of metastasis, a process involving the dissemination of cancer cells to distant organs. Breast cancer metastasis is known to be regulated by caveolin-1 expression and phosphorylation-dependent cell migration. Interestingly, human triple-negative breast cancer cells (MDA-MB-231) uniquely overexpress the K+ channel Kv11.1, providing a potential drug target not present in normal breast epithelia. In these cells, it was shown that treatment of MDA 231 cells with Kv11.1 K+ channel activator NS1643 induced the dephosphorylation of caveolin-1 and resultant dissociation of β-catenin, a crucial regulatory protein for assembly of cell-cell adhesion complexes. Further, NS1643 treatment led to enhanced interaction, assessed by immunoprecipitation and untargeted proteomic analysis, of β-catenin with adherens junction protein R-cadherin, focal adhesion proteins, and desmosomal proteins. These results suggest NS1643-induced β-catenin redistribution away from caveolin-1 enriched membranes to sites of cell-cell and cell-matrix adhesions may enhance or stabilize these complexes and thereby reduce cell migration and metastasis. To begin to test the idea that NS1643 promotes cell adhesions, we treated MDA 231 cells for up to 24 hrs and conducted Western blot analysis of phosphorylated-caveolin-1 (pY14), desmoplakin, desmoglein, and plakophilin proteins, and also measured electrical resistance of cell monolayers grown on gold-plated microelectrodes with an epithelial cell impedance system. Results thus far indicate NS1643 rapidly reduces caveolin-1 phosphorylation and increases the expression of some desmosomal proteins as well as monolayer resistance within 24 hrs. Thus, this study is beginning to reveal a potentially promising pharmacological mechanism for inhibiting breast cancer metastasis by promoting caveolin-1 dephosphorylation-dependent increase in β-catenin supported cell-cell desmosome adhesions.
One of the primary objectives of cancer therapy is the prevention of metastasis, a process involving the dissemination of cancer cells to distant organs. Breast cancer metastasis is known to be regulated by caveolin-1 expression and phosphorylation-dependent cell migration. Interestingly, human triple-negative breast cancer cells (MDA-MB-231) uniquely overexpress the K+ channel Kv11.1, providing a potential drug target not present in normal breast epithelia. In these cells, it was shown that treatment of MDA 231 cells with Kv11.1 K+ channel activator NS1643 induced the dephosphorylation of caveolin-1 and resultant dissociation of β-catenin, a crucial regulatory protein for assembly of cell-cell adhesion complexes. Further, NS1643 treatment led to enhanced interaction, assessed by immunoprecipitation and untargeted proteomic analysis, of β-catenin with adherens junction protein R-cadherin, focal adhesion proteins, and desmosomal proteins. These results suggest NS1643-induced β-catenin redistribution away from caveolin-1 enriched membranes to sites of cell-cell and cell-matrix adhesions may enhance or stabilize these complexes and thereby reduce cell migration and metastasis. To begin to test the idea that NS1643 promotes cell adhesions, we treated MDA 231 cells for up to 24 hrs and conducted Western blot analysis of phosphorylated-caveolin-1 (pY14), desmoplakin, desmoglein, and plakophilin proteins, and also measured electrical resistance of cell monolayers grown on gold-plated microelectrodes with an epithelial cell impedance system. Results thus far indicate NS1643 rapidly reduces caveolin-1 phosphorylation and increases the expression of some desmosomal proteins as well as monolayer resistance within 24 hrs. Thus, this study is beginning to reveal a potentially promising pharmacological mechanism for inhibiting breast cancer metastasis by promoting caveolin-1 dephosphorylation-dependent increase in β-catenin supported cell-cell desmosome adhesions.
