Non‐oxidized and oxidized flaxseed orbitides differently induce HepG2 cell apoptosis: involvement of cellular uptake and membrane death receptor DR4

化学 细胞凋亡 受体 癌细胞 下调和上调 生物化学 癌症 生物 基因 遗传学
作者
Chun-Jin Peng,Jing Li,Allan Z. Zhao,Shuangni Yu,Liqing Zheng,Zeyuan Deng
出处
期刊:Journal of the Science of Food and Agriculture [Wiley]
卷期号:104 (7): 4296-4308
标识
DOI:10.1002/jsfa.13315
摘要

Abstract BACKGROUND Flaxseed orbitides have health‐promoting properties, particularly potent anti‐cancer activity. However, flaxseed orbitides containing a methionine structure, such as [1‐9‐NαC]‐linusorb B2 (CLB), are easily oxidized to sulfoxide ([1‐9‐NαC],[1‐Rs,Ss‐MetO]‐linusorb‐B2 (CLC)) and sulfone ([1–9‐NαC], [1‐MetO]‐linusorb B2 (CLK)), with CLC having less anti‐cancer ability than CLB. It is unclear why oxidized flaxseed orbitides are less effective against cancer than non‐oxidized flaxseed orbitide. RESULTS Non‐oxidized ([1‐9‐NαC]‐linusorb‐B3 (CLA) and CLB) and oxidized (CLC and CLK) flaxseed orbitides were found to significantly upregulate the levels of pro‐apoptotic proteins, including Bax/Bcl‐2, CytoC, caspase‐3, and caspase‐8, in a dose‐dependent manner, with non‐oxidized flaxseed orbitides being more effective than oxidized flaxseed orbitides. Mechanically, the cellular absorption of non‐oxidized flaxseed orbitides was higher than that of oxidized flaxseed orbitides. Moreover, the significant fluorescence quenching of DR4 protein by flaxseed orbitides (especially non‐oxidized orbitides) indicated the formation of a DR4–orbitide complex. Molecular docking demonstrated that non‐oxidized orbitides could easily dock into the active cavity of DR4 protein. Further blocking DR4 significantly reduced the ability of non‐oxidized flaxseed orbitides to stimulate caspase‐3 expression, whereas oxidized flaxseed orbitides retained this ability. CONCLUSION Non‐oxidized flaxseed orbitides are more effective against cancer than oxidized flaxseed orbitides due to higher cellular uptake and activation of the DR4‐mediated death receptor signaling pathway. © 2024 Society of Chemical Industry.
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