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  • Cisplatin resistance in lung cancer is mediated by MACC1 expression through PI3K/AKT signaling pathway activation.

Cisplatin resistance in lung cancer is mediated by MACC1 expression through PI3K/AKT signaling pathway activation.

Acta biochimica et biophysica Sinica (2018-07-03)
Qiang Zhang, Bin Zhang, Leina Sun, Qingna Yan, Yu Zhang, Zhenfa Zhang, Yanjun Su, Changli Wang
ABSTRACT

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. Cisplatin-resistant 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. Western blot analysis and qRT-PCR assays were performed to determine the changes in signaling pathway-related protein and mRNA levels, respectively. A nude mouse xenograft 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.

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MISSION® esiRNA, targeting human MACC1