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In addition to the well-known cardiotonic effects,cardiac glycosides (CGs) produce potent anticancer effects with various molecular mechanisms.We previously show that ouabain induces autophagic cell death in human lung cancer cells by regulating AMPKmediated mTOR and Src-mediated ERK1/2 signaling pathways.However,whether and how AMPK and Src signaling interacts in ouabain-treated cancer cells remains unclear.Given the pivotal role of AMPK in metabolism,whether ouabain affects cancer cell metabolism remains elusive.In this study we showed that treatment with ouabain (25 nM) caused simultaneous activation of AMPK and Src signaling pathways in human lung cancer A549 cells and human breast cancer MCF7 cells.Cotreatment with AMPK inhibitor compound C or siRNA greatly abrogates ouabain-induced Src activation,whereas cotreatment with Src inhibitor PP2 has little effect on ouabain-induced AMPK activity,suggesting that AMPK served as an upstream regulator of the Src signaling pathway.On the other hand,ouabain treatment greatly depletes ATP production in A549 and MCF7 cells,and supplement of ATP (100 μM) blocked ouabain-induced AMPK activation.We further demonstrated that ouabain greatly inhibited the mitochondrial oxidative phosphorylation (OXPHOS) in the cancer cells,and exerted differential metabolic effects on glycolysis depending on cancer cell type.Taken together,this study reveals that the altered cancer cell metabolism caused by ouabain may contribute to AMPK activation,as well as its cytotoxicity towards cancer cells.