title: Loss of presenilin 2 is associated with increased iPLA2 activity and lung tumor development.
abstract: Presenilins are the enzymatic components of γ-secretase complex that cleaves amyloid precursor protein, Notch and β-catenin, which has critical roles in the development of Alzheimer's disease and cancer cell growth. Therefore, in the present study, we studied the effects and mechanisms of PS2 knockout on lung cancer development and possible mechanisms as a key regulator of lung tumor development. We compared carcinogen-induced tumor growth between PS2 knockout mice and wild-type mice. PS2 knockout mice showed increased urethane (1 mg/g)-induced lung tumor incidence when compared with that of wild-type mice with decreased activity of γ-secretase in the lung tumor tissues. Consequently, iPLA2 activities in lung tumor tissues of PS2 knockout mice were much higher than in tumor tissues of wild-type mice. Furthermore, knockdown of PS2 using PS2 siRNA decreased γ-secretase activity with increased iPLA2 activity in the lung cancer cells (A549 and NCI-H460), leading to increased lung cancer cell growth. PS2 knockout mice and PS2 knockdown lung cancer cells showed increased DNA-binding activities of nuclear factor kappa-beta, signal transducer and activator of transcription 3 (STAT3) and AP-1 which are critical transcriptional factors of iPLA2 than those of PS2 wild-type mice and control lung cancer cells. Taken together, these results suggest that the loss of PS2 could have a critical role in lung tumor development through the upregulation of iPLA2 activity by reducing γ-secretase.
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: H-M
authors.initials: HM
authors.lastname: Yun
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: M H
authors.initials: MH
authors.lastname: Park
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: D H
authors.initials: DH
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Ahn
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: K-R
authors.initials: KR
authors.lastname: Park
authors.affiliation: College of Veterinary Medicine, Chungbuk National University, 12, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: T M
authors.initials: TM
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: N Y
authors.initials: NY
authors.lastname: Yun
authors.affiliation: College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeung-gu, Busan, Republic of Korea.
authors.forename: Y S
authors.initials: YS
authors.lastname: Jung
authors.affiliation: Department of Biomaterial Science, Pusan National University, Miryang, Kyungnam, Republic of Korea.
authors.forename: D Y
authors.initials: DY
authors.lastname: Hwang
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Gwangjin-gu, Seoul, Republic of Korea.
authors.forename: D Y
authors.initials: DY
authors.lastname: Yoon
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: S B
authors.initials: SB
authors.lastname: Han
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: J T
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D054465:Peroxiredoxin VI / Q000235:genetics / Q000378:metabolism; D053766:Presenilin-2 / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D016328:NF-kappa B; C508861:PSEN2 protein, human; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D018808:Transcription Factor AP-1; D054465:Peroxiredoxin VI; C515983:Prdx6 protein, mouse; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human; C516476:Pla2g6 protein, mouse