Cholesterol Secosterol Aldehydes Induce Amyloidogenesis and Dysfunction of Wild-Type Tumor Protein p53

Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Chemistry & biology (Impact Factor: 6.65). 07/2011; 18(7):920-7. DOI: 10.1016/j.chembiol.2011.02.018
Source: PubMed


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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    • "The transactivation domain (residues 1–63), when exposed to low pH, formed aggregates enriched in β-sheets, presenting an amyloid pattern as shown by thioflavin T-binding, AFM and X-ray diffraction [18]. Taken together, these findings suggested that the whole protein could aggregate into amyloid assemblies, which was later demonstrated by several groups [19,20,76,77]. "
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    ABSTRACT: p53 is a key protein that participates in cell-cycle control, and its malfunction can lead to cancer. This tumour suppressor protein has three main domains; the N-terminal transactivation domain, the CTD (C-terminal domain) and the core domain (p53C) that constitutes the sequence-specific DBD (DNA-binding region). Most p53 mutations related to cancer development are found in the DBD. Aggregation of p53 into amyloid oligomers and fibrils has been shown. Moreover, amyloid aggregates of both the mutant and WT (wild-type) forms of p53 were detected in tumour tissues. We propose that if p53 aggregation occurred, it would be a crucial aspect of cancer development, as p53 would lose its WT functions in an aggregated state. Mutant p53 can also exert a dominant-negative regulatory effect on WT p53. Herein, we discuss the dominant-negative effect in light of p53 aggregation and the fact that amyloid-like mutant p53 can convert WT p53 into more aggregated species, leading into gain of function in addition to the loss of tumour suppressor function. In summary, the results obtained in the last decade indicate that cancer may have characteristics in common with amyloidogenic and prion diseases.
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    • "The ozonation product of cholesterol (ChSeco) was found to induce Aβ aggregation in a dose-dependent manner [16]. The inflammation-derived cholesterol 5,6-secosterol aldehydes induced the misfolding of wild-type p53 into an amyloidogenic form that binds thioflavin T [17]. In summary, the above-mentioned studies suggest the steroid structure of cholesterol may play an important role in the formation of protein aggregates. "
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    Preview · Article · Sep 2012 · PLoS ONE
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    ABSTRACT: The tumor suppressor p53 plays an important role in genome integrity. It is frequently mutated in all types of human cancers, making p53 a key factor in cancer progression. Two phenotypic consequences of these alterations are dominant; a loss of function and a gain of function of p53, which, in several cases, accumulates in intracellular aggregates. Although the nature of such aggregates is still unclear, recent evidence indicates that p53 can undergo conformational transitions leading to amyloid formation. Amyloid diseases, such as, Alzheimer's disease, are characterized by the accumulation of insoluble aggregates displaying the fibrillar conformation. We decided to investigate the propensity of wild type p53 to aggregate and its consequent assembly into different amyloid species, such as oligomers and fibrils; and to determine if these changes in conformation lead to a loss of function of p53. Furthermore, we analyzed cases of Basal Cell Carcinoma (BCC), for the presence of p53 amyloids. Here, we show that p53 forms amyloid oligomers and fibrils, which coincide with p53 inability of binding to DNA consensus sequences. Both p53 amyloid oligomers and fibrils were detected in BCC cancer samples. Additionally, we demonstrate that p53 oligomers are the most cytotoxic to human cell cultures. Our study reveals p53 amyloid formation and demonstrates its dual role in the pathogenesis of cancer by producing a loss of protein function and a gain of toxic function, extensively described in several amyloidogenic diseases. Our results suggest that under certain circumstances, cancer could be considered a protein-conformation disease.
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