• Anne Forde

Grape Component Promotes Apoptosis in Prostate Cancer

Kai et al., pp. 1538–1548

Resveratrol (Res) has many documented medicinal properties, including anti-cancer effects. In this study, Kai et al., explored whether Res can affect epigenetic silencing processes that are associated with aggressive tumor behavior.

One such process involves metastasis-associated protein 1 (MTA1), a protein whose over-expression correlates with aggressive and metastatic human cancers, including prostate cancer. MTA1 is part of a multiprotein complex which works to maintain a locked chromatin structure by deacetylating proteins such as p53. As a result, p53's apoptotic effects are repressed.

In the present work, Res was shown to inhibit MTA1 protein in prostate cancer cell lines in a dose-dependent manner. Immunoprecipitation showed that Res also destabilized MTA1 within its nucleosome deacetylation complex. This led to a 14-fold higher ratio of acetylated p53 to total p53 in prostate cancer cells.

Silencing MTA1 – using RNA interference – produced only a minor increase in p53 acetylation but it significantly sensitized the cells to Res-dependent p53 acetylation. This in turn led to an increase in pro-apoptotic genes such as Bax and increased observed cellular apoptosis.

This study shows that MTA1 is a target of Res. Res was seen to influence chromatin remodeling and ultimately increase the anti-cancer effects of p53 through promoting p53 acetylation. These results offer an insight into the role of Res in epigenetic gene silencing and are particularly promising as Res is a common dietary component.

p53 Polymorphism and Sensitivity to Chemotherapy

Tominaga et al., pp. 1691–1701

Mutations in p53 can affect patient prognosis in colorectal cancer. A common p53 polymorphism at codon 72 (Arg/Arg, Arg/Pro and Pro/Pro) can also affect the sensitivity of cells to chemotherapeutic agents. This study focuses on the influence of p53 mutations and polymorphism on cellular response to the chemotherapeutic agent 5-fluorouracil, which is important in colorectal cancer treatment.

Using tumor samples from over a hundred patients, sensitivity of the tumor cells to 5-fluorouracil was assessed using a collagen gel droplet-embedded culture test. The most dramatic difference was seen in patients with combinations of p53 polymorphism and ‘hot spot’ p53 mutations known as inactive mutations. Patients with the Arg/Arg polymorphism, tumor cells without inactive p53, were highly sensitive to 5-fluorouracil compared to those with inactive p53 (p = 0.001). However, patients with the other polymorphisms did not gain this advantage even without inactive p53. Even more puzzlingly, patients with Arg/Arg polymorphism and inactive p53 had the least sensitivity to the chemotherapeutic agent (p = 0.002). 5-Fluorouracil sensitivity was associated with increased Bax protein expression and a high apoptotic index.

This is the first report to show the combined influence of p53 polymorphisms with or without inactive p53 mutations on tumor cell sensitivity to 5-fluorouracil. Further prospective studies on the survival of these patients are required, but this work indicates the potential predictive marker that p53 polymorphisms in combination with p53 mutation status can offer regarding tumor sensitivity to 5-fluorouracil.

MicroRNA Expression Profiles of Gastrointestinal Stromal Tumors

Choi et al., pp. 1640–1650

Gastrointestinal stromal tumors (GISTs) have characterized mutations such as KIT and PDGFRA and have fragile genomic sites: loss of chromosome 14q is a common genomic change. Previously the authors observed that gene expression profiles of GISTs are relatively homogenous and may have some association with 14q presence and KIT mutations.

In this report, Choi et al., wanted to look for KIT and PDGFRA mutations, chromosomal loss and microRNA expression in 20 GISTs patients. MicroRNA expression is thought to be related to tumorgenesis; therefore, the authors hoped it might shed some light on the genetic and clinicopathologic characteristics seen in GISTs.

Hierarchical clustering analysis was used to classify the 20 GISTs according to microRNA expression profiles. Patients were clustered into 4 groups. Branch A and B are both high-risk GISTs but are separated from each other by anatomical site of the tumor – small bowel versus stomach. Branches C and D represent stomach GISTs and branch D distinguished itself from all other groups as the only one that didn't have 14q loss. Some 73 microRNAs were significantly downregulated in GISTs with 14q loss – 38 of these were encoded on 14q. Many of the microRNAs downregulated in the high-risk and small-bowel GISTs are associated with cell cycle pathways.

These findings suggest that microRNA expression patterns of GISTs are related to genomic changes and the clinical behavior of the tumor and therefore may be useful for classifying GISTs.1

Illustration 1.

Hierarchical clustering analysis of microRNA expression in 20 GISTs. H = high-risk group, I = intermediate-risk group, L = low-risk group, Sb = small bowel, St = stomach, black box = chromosomal loss, white box = no chromosomal loss, M = mutation positive, W = wild-type.