title: Prx1 modulates the chemosensitivity of lung cancer to docetaxel through suppression of FOXO1-induced apoptosis.
abstract: The expression levels of Prx1 are frequently elevated in several human cancers, including lung cancer and may confer increased resistance to treatment. In this study, we investigated the role of Prx1 in docetaxel-induced apoptosis in A549 lung cancer cells. To test whether Prx1 knockdown affected the sensitivity of A549 cells to docetaxel treatment, we generated short hairpin RNA (shRNA) constructs targeting Prx1 and analyzed the effect of Prx1 knockdown on growth and apoptosis. Tumor growth was evaluated in scrambled shRNA- or shPrx1-infected A549 cell tumors receiving docetaxel treatment. In addition, mechanistic information was gathered by western blot analysis from cell lysates of scrambled- and shPrx1-infected A549 cells pretreated with or without LY294002 and subsequently treated with docetaxel. We found that Prx1 knockdown resulted in enhanced docetaxel-induced cytotoxicity in a dose-dependent manner. In vivo, the growth rate of shPrx1-infected A549 tumors was significantly reduced compared to that of scrambled shRNA-infected A549 tumors. Prx1 knockdown also augmented the inhibitory effects of docetaxel on tumor growth. Prx1 knockdown increased the apoptotic potential through activation of the caspase cascade and suppressed docetaxel-induced phosphorylation of Akt and its substrate forkhead box O1 (FOXO1). Moreover, treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 reduced the phosphorylation of FOXO1 and increased the cytotoxicity of docetaxel in A549 cells. Our findings suggest that Prx1 may modulate the chemosensitivity of lung cancer to docetaxel through suppression of FOXO1-induced apoptosis.
authors.affiliation: Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Ki-Eun
authors.initials: KE
authors.lastname: Hwang
authors.forename: Do-Sim
authors.initials: DS
authors.lastname: Park
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Kim
authors.forename: Byoung-Ryun
authors.initials: BR
authors.lastname: Kim
authors.forename: Seong-Nam
authors.initials: SN
authors.lastname: Park
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Lee
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Park
authors.forename: Kwon-Ha
authors.initials: KH
authors.lastname: Yoon
authors.forename: Eun-Taik
authors.initials: ET
authors.lastname: Jeong
authors.forename: Hak-Ryul
authors.initials: HR
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; C082157:PRRX1 protein, human; D043823:Taxoids; D000077143:Docetaxel; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt