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.
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| http://dx.doi.org/10.1016/j.chembiol.2011.02.018 | DOI Listing |
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Article Synopsis
- Inhalation of ozone, a common air pollutant, leads to lung inflammation and decreases the effectiveness of immune cells called macrophages by affecting their ability to engulf pathogens.
- Ozone reacts with lung cholesterol to create oxysterols (Secosterol A and B) that attach to proteins in macrophages, but the effects of this attachment on macrophage function were previously unclear.
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