Survival of detached cancer cells is regulated by movement of intracellular Na+,K+-ATPase

Takuto Fujii; Takahiro Shimizu; Mizuki Katoh; Shushi Nagamori; Keiichi Koizumi; Junya Fukuoka; Yoshiaki Tabuchi; Akira Sawaguchi; Tomoyuki Okumura; Kazuto Shibuya; Tsutomu Fujii; Hiroshi Takeshima; Hideki Sakai

doi:10.1016/j.isci.2021.102412

Survival of detached cancer cells is regulated by movement of intracellular Na⁺,K⁺-ATPase

iScience. 2021 Apr 15;24(5):102412. doi: 10.1016/j.isci.2021.102412. eCollection 2021 May 21.

Authors

Affiliations

¹ Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
² Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
³ Laboratory of Drug Discovery and Development for Pre-disease, Section of Host Defences, Division of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.
⁴ Laboratory of Pathology, Toyama University Hospital, Toyama 930-0194, Japan.
⁵ Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, Toyama 930-0194, Japan.
⁶ Department of Anatomy, Ultrastructural Cell Biology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
⁷ Department of Surgery and Science, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan.
⁸ Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.

Abstract

Beginning of metastasis, cancer cells detach from the primary tumor and they can survive even under loss of anchorage; however, the detachment-elicited mechanisms have remained unknown. Here, we found that Na⁺,K⁺-ATPase α3-isoform (α3NaK) in human cancer cells is dynamically translocated from intracellular vesicles to the plasma membrane when the attached cells are detached and that this mechanism contributes to the survival of the detached (floating) cancer cells. α3NaK was detected in the plasma membrane of floating cancer cells in peritoneal fluids of patients, while it was in the cytoplasm of the cells in primary tumor tissues. On cancer cell detachment, we also found the focal-adhesion-kinase-dependent Ca²⁺ response that induces the α3NaK translocation via nicotinic acid adenine dinucleotide phosphate pathway. Activation of AMP-activated protein kinase was associated with the translocated α3NaK in the plasma membrane. Collectively, our study identifies a unique mechanism for survival of detached cancer cells, opening up new opportunities for development of cancer medicines.

Keywords: Cancer; Cell Biology.