FXYD5 (dysadherin) may mediate metastatic progression through regulation of the β-Na+-K+-ATPase subunit in the 4T1 mouse breast cancer model

Irina Lubarski-Gotliv; Kuntal Dey; Yuri Kuznetsov; Vecheslav Kalchenco; Carol Asher; Haim Garty

doi:10.1152/ajpcell.00206.2016

FXYD5 (dysadherin) may mediate metastatic progression through regulation of the β-Na⁺-K⁺-ATPase subunit in the 4T1 mouse breast cancer model

Am J Physiol Cell Physiol. 2017 Jul 1;313(1):C108-C117. doi: 10.1152/ajpcell.00206.2016. Epub 2017 May 17.

Authors

Irina Lubarski-Gotliv¹, Kuntal Dey², Yuri Kuznetsov³, Vecheslav Kalchenco³, Carol Asher², Haim Garty²

Affiliations

¹ Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel; and ira.gotliv@gmail.com.
² Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel; and.
³ Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.

PMID: 28515087
DOI: 10.1152/ajpcell.00206.2016

Abstract

FXYD5 is a Na⁺-K⁺-ATPase regulator, expressed in a variety of normal epithelia. In parallel, it has been found to be associated with several types of cancer and effect lethal outcome by promoting metastasis. However, the molecular mechanism underlying FXYD5 mediated invasion has not yet been identified. In this study, using in vivo 4T1 murine breast cancer model, we found that FXYD5-specific shRNA significantly inhibited lung cancer metastasis, without having a substantial effect on primary tumor growth. Our study reveals that FXYD5 participates in multiple stages of metastatic development and exhibits more than one mode of E-cadherin regulation. We provide the first evidence that FXYD5-related morphological changes are mediated through its interaction with Na⁺-K⁺-ATPase. Experiments in cultured 4T1 cells have indicated that FXYD5 expression may downregulate the β1 isoform of the pump. This behavior could have implications on both transcellular interactions and intracellular events. Further studies suggest that differential localization of the adaptor protein Annexin A2 in FXYD5-expressing cells may correlate with matrix metalloproteinase 9 secretion and adhesion changes in 4T1 wild-type cells.

Keywords: 4T1; FXYD5 dysadherin; Na+-K+-ATPase; breast cancer; metastasis.

MeSH terms

Animals
Annexin A2 / genetics
Annexin A2 / metabolism
Cadherins / genetics
Cadherins / metabolism
Cell Adhesion
Cell Line, Tumor
Cell Movement
Disease Models, Animal
Female
Gene Expression Regulation, Neoplastic*
Ion Channels
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / secondary
Mammary Glands, Animal / metabolism
Mammary Glands, Animal / pathology
Mammary Neoplasms, Experimental / genetics*
Mammary Neoplasms, Experimental / metabolism
Mammary Neoplasms, Experimental / pathology
Matrix Metalloproteinase 9 / genetics
Matrix Metalloproteinase 9 / metabolism
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mice
Mice, Inbred BALB C
Microfilament Proteins
Neoplasms, Adipose Tissue / genetics*
Neoplasms, Adipose Tissue / metabolism
Neoplasms, Adipose Tissue / pathology
Protein Subunits / genetics
Protein Subunits / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Sodium-Potassium-Exchanging ATPase / genetics*
Sodium-Potassium-Exchanging ATPase / metabolism

Substances

Annexin A2
Cadherins
Cdh1 protein, mouse
FXYD5 protein, mouse
Ion Channels
Membrane Proteins
Microfilament Proteins
Protein Subunits
RNA, Small Interfering
Matrix Metalloproteinase 9
Mmp9 protein, mouse
Sodium-Potassium-Exchanging ATPase