title: Cholesterol secosterol aldehydes induce amyloidogenesis and dysfunction of wild-type tumor protein p53.
abstract: Epidemiologic and clinical evidence points to an increased risk for cancer when coupled with chronic inflammation. However, the molecular mechanisms that underpin this interrelationship remain largely unresolved. Herein we show that the inflammation-derived cholesterol 5,6-secosterol aldehydes, atheronal-A (KA) and -B (ALD), but not the polyunsaturated fatty acid (PUFA)-derived aldehydes 4-hydroxynonenal (HNE) and 4-hydroxyhexenal (HHE), induce misfolding of wild-type p53 into an amyloidogenic form that binds thioflavin T and Congo red dyes but cannot bind to a consensus DNA sequence. Treatment of lung carcinoma cells with KA and ALD leads to a loss of function of extracted p53, as determined by the analysis of extracted nuclear protein and in activation of p21. Our results uncover a plausible chemical link between inflammation and cancer and expand the already pivotal role of p53 dysfunction and cancer risk.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Nieva
authors.forename: Byeong-Doo
authors.initials: BD
authors.lastname: Song
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Rogel
authors.forename: David
authors.initials: D
authors.lastname: Kujawara
authors.forename: Lawrence
authors.initials: L
authors.lastname: Altobel
authors.forename: Alicia
authors.initials: A
authors.lastname: Izharrudin
authors.forename: Grant E
authors.initials: GE
authors.lastname: Boldt
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Grover
authors.forename: Anita D
authors.initials: AD
authors.lastname: Wentworth
authors.forename: Paul
authors.initials: P
authors.lastname: Wentworth
mesh_terms: D000447:Aldehydes / Q000276:immunology*; D000682:Amyloid / Q000276:immunology*; D002460:Cell Line; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000276:immunology; D004247:DNA / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D017510:Protein Folding; D013261:Sterols / Q000276:immunology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: C479527:5,6-secosterol; D000447:Aldehydes; D000682:Amyloid; D013261:Sterols; D016159:Tumor Suppressor Protein p53; D004247:DNA; D002784:Cholesterol