Notch signaling plays a crucial role in the development of colon cancer; targeting the Notch pathway may sensitize colon cancers to various adjuvant agents. The focus of our current study is to identify natural compounds that target Notch signaling and that might be beneficial for the prevention and treatment of colon cancer. Withaferin-A (WA) is a bioactive compound derived from Withania somnifera, which inhibits Notch-1 signaling and downregulates prosurvival pathways, such as Akt/NF-κB/Bcl-2, in three colon cancer cell lines (HCT-116, SW-480, and SW-620). In addition, WA downregulated the expression of mammalian target of rapamycin signaling components, pS6K and p4E-BP1, and activated c-Jun-NH2-kinase–mediated apoptosis in colon cancer cells. We also established the molecular link between Notch/Akt/mammalian target of rapamycin signaling by complementary approaches (i.e., overexpression of Notch-1 or inhibition of Notch-1 by small interfering RNA). Our results suggest that WA inhibits Notch-mediated prosurvival signaling, which facilitates c-Jun-NH2-kinase–mediated apoptosis in colon cancer cell lines. These results underscore the anticancer activity of WA, which exhibits potential for further development for targeted chemotherapy and/or chemoprevention strategies in the context of colon cancer. Mol Cancer Ther; 9(1); 202–210
A xanthine oxidase‐based system was used to generate hydroxyl free radicals in washed, minced cod muscle. Oxidation of protein was measured by increase in protein carbonyl content; the system used produced approximately 0.1 mol of carbonyl groups per 105 g of protein. This degree of oxidation had only minor effects on the SDS‐PAGE patterns of the muscle proteins. The solubility of the proteins was not affected by this amount of oxidation unless they were also subjected to a freeze/thaw cycle. With a freeze/thaw cycle, a highly significant decrease in protein solubility occurred compared to that which took place in a sample not exposed to the free radical system. Lowering the pH from 6.8 or 6.5 to 6.0 or 5.5 had a strong negative impact on protein solubility. Protein oxidation appeared in two phases in washed cod mince, an initial rapid increase followed by a second phase that may have been linked to oxidation of the small amount of lipid in the sample. Comparison of protein carbonyl formation in stored mackerel fillets or mince indicated that the range of oxidation studied in the cod model system was similar to what occurs in stored mackerel muscle postmortem.
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