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HtrA1 Downregulation Induces Cisplatin Resistance in Lung Adenocarcinoma by Promoting Cancer Stem Cell‐Like Properties

Cisplatin (CDDP) resistance usually develops during lung adenocarcinoma (LAC) therapy. However, the comprehensive mechanisms remain largely unclear. In this study, we first established a CDDP‐resistant LAC cell line‐A549/CDDP from its parental cell line‐A549. The results showed that CDDP resistance in A549/CDDP cells correlates with acquirement of cancer stem cell‐like properties (increased percentage of CD133‐expressing subpopulation, sphere formation and levels of some pluripotency‐associated markers). HtrA1 expression at both mRNA and protein levels was reduced in CDDP‐resistant A549/CDDP cells compared with that in A549 cells. Ectopic expression of HtrA1 in A549/CDDP cells reversed cancer stem cell‐like properties and CDDP resistance. In A549 cells, stable knockdown of HtrA1 expression promoted cancer stem cell‐like properties and CDDP insensitivity, however, these effects were blocked by inhibition of PI3K/Akt pathway using LY294002. Furthermore, HtrA1 knockdown could significantly stimulate PI3K/Akt signaling in A549 cells. In vivo studies, HtrA1 knockdown promoted tumorigenesis and conferred CDDP resistance in xenograft A549 tumors, which were reversed by intraperitoneal injection of LY294002. In conclusion, these results indicate that HtrA1 downregulation confers CDDP resistance by inducing cancer stem cell‐like properties via PI3K/Akt‐dependent pathway in A549 cells. Therefore, HtrA1 may be a potential target for overcoming CDDP resistance in LAC. J. Cell. Biochem. 115: 1112–1121, 2014. © 2013 Wiley Periodicals, Inc.