The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice

Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitro and in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA- MB- 231 cells in correlation with reduced activation of the survival pathway NF kappa B, as a consequence of diminished I kappa B and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NF kappa B activity and transcriptional downregulation of AP-1. NF kappa B/p65 silencing is sufficient to downregulate c-jun and MMP expression. Reduced NF kappa B/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NF kappa B/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible. Copyright (c) 2007 S. Karger AG, Basel

Achlya mitochondrial DNA: gene localization and analysis of inverted repeats

Mitochondrial DNA from four strains of the oomycete Achlya has been compared and nine gene loci mapped, including that of the ribosomal protein gene, var1 . Examination of the restriction enzyme site maps showed the presence of four insertions relative to a map common to all four strains. All the insertions were found in close proximity to genic regions. The four strains also cotained the inverted repeat first observed in A. ambisexualis (Hudspeth et al. 1983), allowing an examination by analysis of retained restriction sites of the evolutionary stability of repeated DNA sequences relative to single copy sequences. Although the inverted repeat is significantly more stable than single copy sequences, more detailed analysis indicated that this stability is limited to the portion encoding the ribosomal RNA genes. Thus, the apparent evolutionary stability of the repeat does not appear to derive from the inverted repeat structure per se.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47563/1/438_2004_Article_BF00330510.pd

Novel roles for GAPDH in cell death and carcinogenesis

Publicado en línea el 25 de septiembre de 2009Growing evidence points to the fact that glucose metabolism has a central role in carcinogenesis. Among the enzymes controlling this energy production pathway, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is of particular interest. Initially identified as a glycolytic enzyme and considered as a housekeeping gene, this enzyme is actually tightly regulated and is involved in numerous cellular functions. Particularly intriguing are recent reports describing GAPDH as a regulator of cell death. However, its role in cell death is unclear; whereas some studies point toward a proapoptotic function, others describe a protective role and suggest its participation in tumor progression. In this study, we highlight recent findings and discuss potential mechanisms through which cells regulate GAPDH to fulfill its diverse functions to influence cell fate.This work was supported in part by l’Association pour la Recherche sur le Cancer, by l’Agence Nationnal de la Recherche, la Fondation de France, Plan Nacional I+D SAF2008-04974 and by grants from The U.S. National Institutes of Health. J-E.R. is a recipient of a contrat d’interface INSERM-CHU de Nice.Peer reviewe