Mutations in genes functioning in different pathways frequently occur together in the same cancer, whereas mutations in the same pathway tend to be mutually exclusive. However, the majority of colon, breast, and endometrial cancers that possess mutations in PIK3CA, the catalytic subunit p110A of phosphatidylinositol 3 ¶-kinase (PI3K), also possess mutations or alterations in genes upstream of PI3K such as Ras, ERBB2/ ERBB3, or PTEN. PIK3CA mutations occur almost exclusively in invasive tumors, whereas upstream mutations occur as frequently in early-stage and late-stage tumors, suggesting that PIK3CA mutation is a late-stage event that may augment earlier activation of the PI3K pathway. Consistent with this, we find that levels of p-AKT (Ser 473 ) induced by mutant Ras or knockdown of PTEN were dramatically increased by addition of mutant PIK3CA. Soft agar assays revealed that anchorageindependent growth induced by mutant Ras was greatly increased in the presence of mutant PIK3CA. In breast, colon, and endometrial cancers in which the PI3K pathway is activated by a combination of mutant PIK3CA and alterations in Ras, ERBB2/3, or PTEN, signaling to downstream elements such as Akt was mediated exclusively by the p110A isoform, rather than a combination of different PI3K isoforms. Our data therefore suggest that in tumors with co-occurring mutations in multiple components of the PI3K pathway, selective inhibition of the A isoform of p110 is an attractive therapeutic strategy, especially for late-stage tumors.
BACKGROUND: The phosphatidylinositol 3 0 -kinase (PI3K) -AKT pathway is activated in many human cancers and plays a key role in cell proliferation and survival. A mutation (E17K) in the pleckstrin homology domain of the AKT1 results in constitutive AKT1 activation by means of localisation to the plasma membrane. The AKT1 (E17K) mutation has been reported in some tumour types (breast, colorectal, ovarian and lung cancers), and it is of interest which tumour types other than those possess the E17K mutation. METHODS: We analysed the presence of the AKT1 (E17K) mutation in 89 endometrial cancer tissue specimens and in 12 endometrial cancer cell lines by PCR and direct sequencing. RESULTS: We detected two AKT1 (E17K) mutations in the tissue samples (2 out of 89) and no mutations in the cell lines. These two AKT1 mutant tumours do not possess any mutations in PIK3CA, PTEN and K-Ras. INTERPRETATION: Our results and earlier reports suggest that AKT1 mutations might be mutually exclusive with other PI3K -AKTactivating alterations, although PIK3CA mutations frequently coexist with other alterations (such as HER2, K-Ras and PTEN) in several types of tumours.
We studied the effect of tea polyphenols on histamine release from rat basophilic leukemia (RBL-2H3) cells. Among tea polyphenols, (-)- epigallocatechin gallate (EGCG) most strongly and dose-dependently inhibited histamine release from cells stimulated with a calcium ionophore, A23187. (-)-Epigallocatechin (EGC) and (-)-epicatechin gallate (ECG) with a triphenol residue moderately inhibited histamine release, whereas diphenolic (+)-catechin (C) and (-)-epicatechin (EC) did not. The magnitude of the inhibitory effect was in the order EGCG > ECG > EGC. Among simple polyphenols, the triphenol compounds, pyrogallol (PG) and gallic acid (GA) exerted inhibitory activity, but the diphenols, pyrocatechol, hydroquinone, and resorcinol did not. In addition, the mixture of PG and GA inhibited histamine release as strongly as EGCG with two triphenol residues. Similarly, they inhibited histamine release induced by IgE-antigen complex stimulation more efficiently than that induced by A23187 stimulation. EGCG did not inhibit the increase of intracellular Ca2+ in RBL-2H3 cells stimulated with A23187 or IgE antigen. These results indicate that the triphenol structure plays an important role in the inhibitory activity of tea polyphenols. Their activity seemed to be exerted through the metabolic events occurring after the elevation of intracellular Ca2+ concentration.
Irrigation with moderate salinity stress in a hydroponic system improves the inner and outer fruit quality of tomato (Solanum lycopersicon Mill. 'House Momotaro'). We investigated the effects of 50 mM NaCl in a hydroponic solution on the levels of various metabolites, including soluble sugars, amino acids, and organic acids, and on the expression levels of salinity-responsive genes during fruit development. Under salinity, Brix (%), surface color density, and flesh firmness of the fruit were significantly enhanced, whereas fruit enlargement was suppressed. Salinity stress strongly promoted the accumulation of sucrose, citrate, malate, and glutamate, and slightly promoted glucose and γ-amino butyric acid in red fruit. At the transcriptional level, up-regulation of ethylene-synthetic 1-aminocyclopropane-1-carboxylate oxidase and down-regulation of photosynthetic chlorophyll a/b binding protein Cab-1B occurred earlier in stressed fruit than in control fruit. Additionally, the carotenoidbiosynthesis regulatory gene, Phytoene synthase 1, and phosphoenolpyruvate carboxykinase (PEPCK) were upregulated under moderate salinity in the red stage. The expression profiles of these genes in stress-treated fruit were consistent with the changes in fruit quality, including earlier ripening and a deeper red color. Furthermore, the up-regulation of PEPCK suggested that gluconeogenesis is involved in the accumulation of sugars in salinitystressed fruit.
The PI3K (phosphatidylinositol-3-kinase)/mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT-activating genetic alterations. We examined the antitumor effect of NVP-BEZ235—a dual PI3K/mTOR inhibitor—and RAD001—an mTOR inhibitor—in 13 endometrial cancer cell lines, all of which possess one or more alterations in PTEN, PIK3CA, and K-Ras. We also combined these compounds with a MAPK pathway inhibitor (PD98059 or UO126) in cell lines with K-Ras alterations (mutations or amplification). PTEN mutant cell lines without K-Ras alterations (n = 9) were more sensitive to both RAD001 and NVP-BEZ235 than were cell lines with K-Ras alterations (n = 4). Dose-dependent growth suppression was more drastically induced by NVP-BEZ235 than by RAD001 in the sensitive cell lines. G1 arrest was induced by NVP-BEZ235 in a dose-dependent manner. We observed in vivo antitumor activity of both RAD001 and NVP-BEZ235 in nude mice. The presence of a MEK inhibitor, PD98059 or UO126, sensitized the K-Ras mutant cells to NVP-BEZ235. Robust growth suppression by NVP-BEZ235 suggests that a dual PI3K/mTOR inhibitor is a promising therapeutic for endometrial carcinomas. Our data suggest that mutational statuses of PTEN and K-Ras might be useful predictors of sensitivity to NVP-BEZ235 in certain endometrial carcinomas.
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