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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.
AuthorsJorge Nieva, Byeong-Doo Song, Joseph K Rogel, David Kujawara, Lawrence Altobel 3rd, Alicia Izharrudin, Grant E Boldt, Rajesh K Grover, Anita D Wentworth, Paul Wentworth Jr
JournalChemistry & biology (Chem Biol) Vol. 18 Issue 7 Pg. 920-7 (Jul 29 2011) ISSN: 1879-1301 [Electronic] United States
PMID21802012 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier Ltd. All rights reserved.
Chemical References
  • 5,6-secosterol
  • Aldehydes
  • Amyloid
  • Sterols
  • Tumor Suppressor Protein p53
  • DNA
  • Cholesterol
Topics
  • Aldehydes (immunology)
  • Amyloid (immunology)
  • Cell Line
  • Cholesterol (analogs & derivatives, immunology)
  • DNA (metabolism)
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms (genetics, immunology, metabolism)
  • Models, Molecular
  • Protein Binding
  • Protein Folding
  • Sterols (immunology)
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 (chemistry, genetics, immunology, metabolism)

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