Epibrassinolide (EBR), a polyhydroxysteroid belongs to plant growth regulator family, brassinosteroids and has been shown to have a similar chemical structure to mammalian steroid hormones. Our findings indicated that EBR could trigger apoptosis in cancer cells via induction of endoplasmic reticulum (ER) stress, caused by protein folding disturbance in the ER. Normal cells exhibited a remarkable resistance to EBR treatment and avoid from apoptotic cell death. The unfolded protein response clears un/misfolded proteins and restore ER functions. When stress is chronic, cells tend to die due to improper cellular functions. To understand the effect of EBR in non-malign cells, mouse embryonic fibroblast (MEF) cells were investigated in detail for ER stress biomarkers, autophagy, and polyamine metabolism in this study. Evolutionary conserved autophagy mechanism is a crucial cellular process to clean damaged organelles and protein aggregates through lysosome under the control of autophagy-related genes (ATGs). Cells tend to activate autophagy to promote cell survival under stress conditions. Polyamines are polycationic molecules playing a role in the homeostasis of important cellular events such as cell survival, growth, and, proliferation. The administration of PAs has been markedly extended the lifespan of various organisms via inducing autophagy and inhibiting oxidative stress. Our data indicated that ER stress is induced following EBR treatment in MEF cells as well as MEF Atg5^−/− cells. In addition, autophagy is activated following EBR treatment by targeting PI3K/Akt/mTOR in wildtype (wt) cells. However, EBR-induced autophagy targets ULK1 in MEF cells lacking Atg5 expression. Besides, EBR treatment depleted the PA pool in MEF cells through the alterations of metabolic enzymes. The administration of Spd with EBR further increased autophagic vacuole formation. In conclusion, EBR is an anticancer drug candidate with selective cytotoxicity for cancer cells, in addition the induction of autophagy and PA metabolism are critical for responses of normal cells against EBR.

中文翻译：

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Epibrassinolide诱导的自噬以依赖Atg5的方式发生，这归因于MEF细胞中的内质应激诱导。

Epibrassinolide（EBR），一种多羟基类固醇，属于植物生长调节剂家族，属于油菜素类固醇，已被证明具有与哺乳动物类固醇激素相似的化学结构。我们的研究结果表明，EBR可能通过诱导内质网（ER）的蛋白质折叠紊乱引起的内质网（ER）应激来触发癌细胞凋亡。正常细胞表现出对EBR处理的显着抵抗力，避免了凋亡细胞的死亡。展开的蛋白质反应可清除未折叠/错误折叠的蛋白质并恢复ER功能。当压力为慢性时，由于细胞功能不当，细胞倾向于死亡。为了了解EBR在非恶性细胞中的作用，在这项研究中详细研究了小鼠胚胎成纤维细胞（MEF）细胞的ER应激生物标志物，自噬和多胺代谢。进化保守的自噬机制是在自噬相关基因（ATG）的控制下，通过溶酶体清除受损细胞器和蛋白质聚集体的关键细胞过程。在压力条件下，细胞倾向于激活自噬以促进细胞存活。多胺是在重要细胞事件（例如细胞存活，生长和增殖）的稳态中起作用的聚阳离子分子。通过诱导自噬和抑制氧化应激，PA的施用已显着延长了各种生物的寿命。我们的数据表明，在MEF细胞以及MEF Atg5中进行EBR处理后会诱发ER应激 在压力条件下，细胞倾向于激活自噬以促进细胞存活。多胺是在重要细胞事件（例如细胞存活，生长和增殖）的稳态中起作用的聚阳离子分子。通过诱导自噬和抑制氧化应激，PA的施用已显着延长了各种生物的寿命。我们的数据表明，在EF处理后，MEF细胞以及MEF Atg5诱导了ER应激 在压力条件下，细胞倾向于激活自噬以促进细胞存活。多胺是在重要细胞事件（例如细胞存活，生长和增殖）的稳态中起作用的聚阳离子分子。通过诱导自噬和抑制氧化应激，PA的施用已显着延长了各种生物的寿命。我们的数据表明，在MEF细胞以及MEF Atg5中进行EBR处理后会诱发ER应激^-/-细胞。此外，在EBR处理后，通过在野生型（wt）细胞中靶向PI3K / Akt / mTOR激活自噬。但是，EBR诱导的自噬作用在缺少Atg5表达的MEF细胞中靶向ULK1。此外，EBR处理通过代谢酶的改变耗尽了MEF细胞中的PA库。Spd与EBR的管理进一步增加了自噬泡的形成。总之，EBR是一种对癌细胞具有选择性细胞毒性的抗癌药物，此外，自噬和PA代谢的诱导对于正常细胞对EBR的反应至关重要。