Evidence for a potential tumor suppressor role for the Na,K-ATPase beta1-subunit.
The Na,K-ATPase, consisting of two essential subunits (alpha, beta), plays a critical role in the regulation of ion homeostasis in mammalian cells. Recent studies indicate that reduced expression of the beta1 isoform (NaK-beta1) is commonly observed in carcinoma and is associated with events involved in cancer progression. In this study, we present evidence that repletion of NaK-beta1 in Moloney sarcoma virus-transformed Madin-Darby canine kidney cells (MSV-MDCK), a highly tumorigenic cell line, inhibits anchorage independent growth and suppresses tumor formation in immunocompromised mice. Additionally, using an in vitro cell-cell aggregation assay, we showed that cell aggregates of NaK-beta1 subunit expressing MSV-MDCK cells have reduced extracellular regulated kinase (ERK) 1/2 activity compared with parental MSV-MDCK cells. Finally, using immunohistochemistry and fully quantitative image analysis approaches, we showed that the levels of phosphorylated ERK 1/2 are inversely correlated to the NaK-beta1 levels in the tumors. These findings reveal for the first time that NaK-beta1 has a potential tumor-suppressor function in epithelial cells.
Inge
L J
LJ
Department of Pathology and Laboratory Medicine, Molecular Biology Institute, Jonsson Comprehensive Cancer Center-David Geffen School of Medicine, University of California, Los Angeles, California, USA.
Rajasekaran
S A
SA
Yoshimoto
K
K
Mischel
P S
PS
McBride
W
W
Landaw
E
E
Rajasekaran
A K
AK
D000818:Animals; D002448:Cell Adhesion; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D004285:Dogs; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology; D051379:Mice; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008980:Moloney murine sarcoma virus / Q000502:physiology; D010766:Phosphorylation; D021122:Protein Subunits / Q000378:metabolism / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D014183:Transplantation, Heterologous; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D021122:Protein Subunits; D025521:Tumor Suppressor Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000254:Sodium-Potassium-Exchanging ATPase