Metastasis is a major cause of cancer morbidity and mortality. Cancer cells can avoid detachment-induced apoptosis (anoikis) and survive under floating conditions. However, the mechanism by which cancer cells evade anoikis has not been fully established.
Here, we found that intracellular Na⁺,K⁺-ATPase α3-isoform (α3NaK) was abnormally expressed in intracellular vesicles of human cancer cells. Interestingly, the α3NaK-containing vesicles were translocated to the plasma membrane (PM) upon loss of anchorage. Pharmacological and biochemical studies showed that the translocation of α3NaK is mediated by FAK- and NAADP-dependent Ca²⁺ mobilization. The PM expression of α3NaK was also found in metastatic cancer cells obtained from peritoneal fluids of gastric and colon cancer patients. The α3NaK knockdown accelerated the detachment-induced apoptosis of cancer cells. In the mouse model, overexpression of α3NaK significantly inhibited cancer cell growth and lung metastasis. In downstream of the PM-translocated α3NaK, AMPK was found to be phosphorylated (pAMPK). These results suggest that intracellular α3NaK is translocated to PM via detachment-induced FAK/NAADP/Ca²⁺ pathway and that the PM-α3NaK and pAMPK are contributed to the survival of the detached cancer cells.