PPARγ induces growth inhibition and apoptosis through upregulation of insulin-like growth factor-binding protein-3 in gastric cancer cells

Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated transcriptional factor involved in the carcinogenesis of various cancers. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor suppressor gene that has anti-apoptotic activity. The purpose of this study was to investigate the anticancer mechanism of PPARγ with respect to IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed exhibited growth inhibition, induction of apoptosis, and a significant increase in IGFBP-3 expression. We investigated the underlying molecular mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells, suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795). This suggests that the critical PPARγ-response region is located within the p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53 expression. Taken together, these data suggest that PPARγ exhibits its anticancer effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor suppressor.

PPARγ induces growth inhibition and apoptosis through upregulation of insulin-like growth factor-binding protein-3 in gastric cancer cells.

Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated transcriptional factor involved in the carcinogenesis of various cancers. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor suppressor gene that has anti-apoptotic activity. The purpose of this study was to investigate the anticancer mechanism of PPARγ with respect to IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed exhibited growth inhibition, induction of apoptosis, and a significant increase in IGFBP-3 expression. We investigated the underlying molecular mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells, suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795). This suggests that the critical PPARγ-response region is located within the p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53 expression. Taken together, these data suggest that PPARγ exhibits its anticancer effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor suppressor.

First Report of the Armillaria Root-Disease Pathogen, Armillaria gallica, Associated with Several Woody Hosts in Three States of Mexico.

In September 2007, rhizomorphs with morphological characteristics of Armillaria were collected from woody hosts in forests of Mexico State, Veracruz, and Oaxaca, Mexico. Based on pairing tests, isolates were assigned to five somatically compatible genets or clones (MEX7R, MEX11R, MEX23R, MEX28R, and MEX30R). These genets were all identified as Armillaria gallica based on somatic pairing tests against known tester isolates and nucleotide sequences of the translation elongation factor 1α (tef-1α; GenBank Accession Nos. KF156772 to 76). Sequences of tef-1α for all genets showed a max identity of 97 to 99% to A. gallica (ST23, JF313125) (3,4). However, A. gallica comprises a genetically diverse complex that likely represents multiple cryptic species (3). In Mexico, this species has been previously reported in northeastern Morelos on Quercus sp., eastern Mexico State on Pinus hartwegii, and southwestern Mexico State on Prunus persica (1,2). This study identified associations with 10 new hosts within three states of Mexico, but only five hosts were diseased. Genet MEX7R comprised seven isolates collected in the University of Chapingo forest near Texcoco, Mexico State (19°18'10.764″ N, 98°42'14.147″ W, elevation 3441 m). Four MEX7R isolates were collected from diseased Alnus sp. including the root ball of a 130 cm dbh, root-disease killed tree, one isolate from a symptomless Senecio sp. s.l. (Roldana sp.) shrub and two isolates from symptomless Abies religiosa. Genet MEX11R comprised four isolates from a cloud forest near Xalapa, Veracruz (19°31'14.628″ N, 96°59'22.812″ W, elevation 1496 m). MEX11R isolates were collected from the roots of a root-disease killed Carpinus caroliniana, and from trees with no obvious symptoms (Miconia mexicana, Quercus xalapensis, and Liquidambar styraciflua). Two isolates of genet MEX23R were collected from the Jardin Botanico Francisco Javier Clavijero, Instituto de Ecologia, A.C., Xalapa, Veracruz (19°30'49.067″ N, 96°56'32.999″ W, elevation 1344 m). These isolates were from root-diseased Eriobotrya japonica (non-native fruit tree) that showed obvious symptoms (flaccid, chlorotic, and senescing leaves) and from an adjacent, infected Platanus mexicana that did not show readily observable symptoms. Two collections near Oaxaca, Oaxaca, included a single isolate MEX28R from the root ball of a recently root disease-killed Arbutus xalapensis within a small root disease center at Peña Prieta, in Parque La Cumbre, near Ixtepeji (17°09'42.084″ N, 96°38'15.936″ W, elevation 2853 m) and a single isolate MEX30R from the base of an asymptomatic Alnus acuminata near the El Carrizal fish hatchery 10 km northeast of San Miguel del Valle (17°06'45.036″ N, 96°24'03.743″ W, elevation 2594 m). Armillaria gallica has a circumpolar distribution with an extremely wide host range, and its ecological behavior varies greatly. Continued surveys are needed to better understand the distribution and ecological impacts of this pathogen in relation to Armillaria root disease in Mexico and the potential influences of climate change. Although A. gallica displays diverse ecological behavior, trees infected with A. gallica are less likely to survive the stresses of human activity and a changing climate (4). References: (1) D. Alvarado-Rosales and R. A. Blanchette. Phytopathology 84:1106, 1994. (2) R. D. Elias-Roman et al. For. Pathol. 43:390, 2013. (3) M.-S. Kim et al. Phytopathology 102:S4.63, 2012. (4) B. Marcais and N. Breda. J. Ecol. 94:1214, 2006.

First Report of Armillaria Root Disease Caused by Armillaria tabescens on Araucaria araucana in Veracruz, Mexico.

In September 2007, bark samples were collected from the root collar of a single Araucaria araucana tree that had recently died and was suspected of being killed by Armillaria root disease. Disease symptoms and signs included a thinning crown and fruiting bodies at the tree base over a several-year period before tree death. The tree was located in an isolated street-tree planting within a business district on Maestros Veracruzanos Street, Xalapa, Veracruz (19°31'52''N, 96°54'25''W, elevation 1,392 m). One fungal isolate (MEX21WF) was obtained, which possessed two sequence repeat types from the intergenic spacer-1 (IGS-1) region (GenBank Accession Nos. GQ335541 and GQ335542). On the basis of these IGS-1 sequences, this isolate from Mexico possessed 99% nucleotide sequence identities with North American Armillaria tabescens isolates (GenBank Accession Nos. AY695410 ≈ GQ335541 and AY773966 ≈ GQ335542). Somatic pairing tests of the isolate with other North American Armillaria species also identified it as A. tabescens (2). In addition, fruiting bodies were produced on the stump base in 2009 that matched morphological features of A. tabescens, e.g., exannulate, cespitose growth in clusters, brown-gray stipe to blackish toward the base, longitudinally fibrillose, basidiospores (6-) 7 to 9 × 4 to 5 (-5.5) µm, and other general morphology. On the basis of these three lines of taxonomic evidence, it was concluded that the isolate was A. tabescens. To our knowledge, this is the first confirmed report of A. tabescens causing Armillaria root disease in Mexico. Furthermore, this note represents the first report of A. tabescens on Araucaria araucana, which is native to Chile and Argentina. The other previous reports of A. tabescens in Mexico are based on herbarium specimens collected in 1965 (BPI 753040) from Valle de Bravo (approximately 350 km west of Xalapa) in the state of México and 1973 (BPI 753041) from near Monterrey (approximately 760 km north-northwest of Xalapa) in the state of Nuevo León (1). However, no host information or confirmation of taxonomic identification was reported for these herbarium specimens. Although this note confirms the presence of A. tabescens in Mexico, more surveys and monitoring are needed to determine the full distribution of this pathogen in Mexico. Because the climate and tree communities of eastern Mexico are similar to those of the southeastern United States, where A. tabescens has been reported as a common pathogen of oaks and fruit trees (3,4), it seems reasonable that A. tabescens may represent an existing or potential threat in eastern Mexico. References: (1) D. F. Farr and A. Y. Rossman. Fungal Databases. Systematic Mycology and Microbiology Laboratory. Online publication. ARS, USDA, 2010. (2) K. I. Mallett and Y. Hiratsuka. Can. J. Bot. 64:2588, 1986. (3) F. Miranda and A. J. Sharp. Ecology 31:313, 1950. (4) G. Schnabel et al. Mycol. Res. 109:1208, 2005.

Reversible Fanconi syndrome associated with valproate therapy.

Two children with developmental delay and seizure disorders had Fanconi syndrome associated with valproate therapy. Both recovered normal proximal tubular function within 4 months of discontinuing valproate therapy.