Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells

<p>Abstract</p> <p>Background</p> <p>Ginger (<it>Zingiber officinale </it>Rosc) is a natural dietary component with antioxidant and anticarcinogenic properties. The ginger component [6]-gingerol has been shown to exert anti-inflammatory effects through mediation of NF-κB. NF-κB can be constitutively activated in epithelial ovarian cancer cells and may contribute towards increased transcription and translation of angiogenic factors. In the present study, we investigated the effect of ginger on tumor cell growth and modulation of angiogenic factors in ovarian cancer cells <it>in vitro</it>.</p> <p>Methods</p> <p>The effect of ginger and the major ginger components on cell growth was determined in a panel of epithelial ovarian cancer cell lines. Activation of NF-κB and and production of VEGF and IL-8 was determined in the presence or absence of ginger.</p> <p>Results</p> <p>Ginger treatment of cultured ovarian cancer cells induced profound growth inhibition in all cell lines tested. We found that <it>in vitro</it>, 6-shogaol is the most active of the individual ginger components tested. Ginger treatment resulted in inhibition of NF-kB activation as well as diminished secretion of VEGF and IL-8.</p> <p>Conclusion</p> <p>Ginger inhibits growth and modulates secretion of angiogenic factors in ovarian cancer cells. The use of dietary agents such as ginger may have potential in the treatment and prevention of ovarian cancer.</p

Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5

ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5+/m) mice that were haploinsuffficient for Atad5. Atad5+/m mice displayed high levels of genomic instability in vivo, and Atad5+/m mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient Atad5+/m mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the Atad5+/m mice. Consistent with a role for Atad5 in suppressing tumorigenesis, we also identified somatic mutations of ATAD5 in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian Atad5 are sufficient to cause genomic instability and tumorigenesis

Sequencing of Candidate Chromosome Instability Genes in Endometrial Cancers Reveals Somatic Mutations in <i>ESCO1</i>, <i>CHTF18</i>, and <i>MRE11A</i>

<div><p>Most endometrial cancers can be classified histologically as endometrioid, serous, or clear cell. Non-endometrioid endometrial cancers (NEECs; serous and clear cell) are the most clinically aggressive of the three major histotypes and are characterized by aneuploidy, a feature of chromosome instability. The genetic alterations that underlie chromosome instability in endometrial cancer are poorly understood. In the present study, we used Sanger sequencing to search for nucleotide variants in the coding exons and splice junctions of 21 candidate chromosome instability genes, including 19 genes implicated in sister chromatid cohesion, from 24 primary, microsatellite-stable NEECs. Somatic mutations were verified by sequencing matched normal DNAs. We subsequently resequenced mutated genes from 41 additional NEECs as well as 42 endometrioid ECs (EECs). We uncovered nonsynonymous somatic mutations in <i>ESCO1</i>, <i>CHTF18,</i> and <i>MRE11A</i> in, respectively, 3.7% (4 of 107), 1.9% (2 of 107), and 1.9% (2 of 107) of endometrial tumors. Overall, 7.7% (5 of 65) of NEECs and 2.4% (1 of 42) of EECs had somatically mutated one or more of the three genes. A subset of mutations are predicted to impact protein function. The co-occurrence of somatic mutations in <i>ESCO1</i> and <i>CHTF18</i> was statistically significant (<i>P</i> = 0.0011, two-tailed Fisher's exact test). This is the first report of somatic mutations within <i>ESCO1</i> and <i>CHTF18</i> in endometrial tumors and of <i>MRE11A</i> mutations in microsatellite-stable endometrial tumors. Our findings warrant future studies to determine whether these mutations are driver events that contribute to the pathogenesis of endometrial cancer.</p></div

Nonsynonymous, somatic mutations in <i>ESCO1</i>, <i>CHTF18</i> and <i>MRE11A</i>, in ECs.

†<p>Case no T3 is also known as OM-1323.</p><p>n/a Not applicable.</p>§<p>Transcript accession numbers: <i>ESCO1</i> (NM_052911.1), <i>CHTF18</i> (NM_022092.1), <i>MRE11A</i> (NM_005591).</p>¶<p>Protein accession numbers: ESCO1 (NP_443143.2), CHTF18 (NP_071375.1), MRE11A (NP_005582.1).</p

Co-occurrence of <i>ESCO1</i> mutations with <i>CHTF18</i> or <i>ATAD5</i> mutations in EC.

§<p>Two-tailed Fisher's exact test.</p