Fujii Takuto, Shimizu Takahiro, Katoh Mizuki, Nagamori Shushi, Koizumi Keiichi, Fukuoka Junya, Tabuchi Yoshiaki, Sawaguchi Akira, Okumura Tomoyuki, Shibuya Kazuto, Fujii Tsutomu, Takeshima Hiroshi, Sakai Hideki
Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
iScience. 2021 Apr 15;24(5):102412. doi: 10.1016/j.isci.2021.102412. eCollection 2021 May 21.
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 Ca 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.
在转移开始时，癌细胞从原发肿瘤脱离，即使在失去锚定的情况下也能存活；然而，脱离引发的机制仍不清楚。在这里，我们发现人类癌细胞中的钠钾ATP酶α3同工型（α3NaK）在贴壁细胞脱离时会从细胞内囊泡动态转运至质膜，并且这一机制有助于脱离（漂浮）癌细胞的存活。在患者腹腔积液中漂浮癌细胞的质膜中检测到α3NaK，而在原发肿瘤组织细胞的细胞质中也存在。在癌细胞脱离时，我们还发现了粘着斑激酶依赖性钙反应，该反应通过磷酸烟酰胺腺嘌呤二核苷酸途径诱导α3NaK转运。AMP激活的蛋白激酶的激活与质膜中转运的α3NaK相关。总的来说，我们的研究确定了脱离癌细胞存活的独特机制，为癌症药物的开发开辟了新的机会。
