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One of the major obstacles hindering the treatment of lung cancer (LC) is chemoresistance;however,its mechanism remains unclear.The overexpression of the metastasis-associated in colon cancer 1 (MACC1) gene has been demonstrated to reverse chemoresistance.In the current study,the expression of MACC1 in LC cells with cisplatin resistance (Cis-Re) was investigated.Cisplatinresistant cell sublines (A549/CR and H446/CR) were induced by stepwise escalation of cisplatin exposure.MTS and flow cytometry assays were performed to measure cell proliferation and apoptosis,respectively.Weste blot analysis and qRT-PCR assays were performed to determine the changes in signaling pathway-related protein and mRNA levels,respectively.A nude mousexenograft model was used for in vivo experiments.Our results showed that MACC1 expression was increased in the cisplatin-resistant A549/CR and H446/CR cell lines,and the resistance was reversed with a decrease of MACC1 expression.MACC1 overexpression triggered an increase of Cis-Re,which was contrary to the effect of MACC1 down-regulation.In addition,the effect of MACC1 on Cis-Re was blocked by the inhibition of the PI3K/AKT pathway,and treatment with both cisplatin and a PI3K/AKT inhibitor effectively inhibited tumor growth in xenografts with MACC1 overexpression.In conclusion,our results revealed that MACC1 increased Cis-Re partially via the PI3K/AKT signaling pathway,suggesting that MACC1 could serve as a potential target to overcome Cis-Re.Furthermore,combination therapy could alleviate Cis-Re resulted from MACC1 overexpression in patients with LC.