title: HtrA1 downregulation induces cisplatin resistance in lung adenocarcinoma by promoting cancer stem cell-like properties.
abstract: 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.
authors.affiliation: Department of Critical-care Medicine, Qianfoshan Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of, China.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Xu
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Jiang
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Zhang
authors.forename: Nannan
authors.initials: N
authors.lastname: Sun
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Xie
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Hou
authors.forename: Dawei
authors.initials: D
authors.lastname: Wu
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D002945:Cisplatin; D004791:Enzyme Inhibitors; D000074289:High-Temperature Requirement A Serine Peptidase 1; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012697:Serine Endopeptidases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C474012:HTRA1 protein, human
keywords: CANCER STEM CELL; CISPLATIN; HtrA1; LUNG ADENOCARCINOMA; PI3K/Akt