Engeletin suppresses lung cancer progression by inducing apoptotic cell death through modulating the XIAP signaling pathway: A molecular mechanism involving ER stress - 18/06/20
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Graphical abstract |
Highlights |
• | Engeletin reduces the proliferation and induces apoptosis in lung cancer cells. |
• | Engeletin inhibits XIAP expression levels in lung cancer cells. |
• | Engeletin promotes the XIAP ubiquitination to suppress XIAP expression in lung cancer cells. |
• | Engeletin regulates the interaction between XIAP and SMAC in lung cancer cells via meditating ER stress. |
Abstract |
Lung cancer is a leading cause of human death worldwide. Nevertheless, the outcome of present therapeutic options is still not satisfying. Engeletin (ENG, dihydrokaempferol 3-rhamnoside) is a flavanonol glycoside, showing anticancer activities in some tumors. But the exact molecular mechanism of ENG is not fully understood. In our present study, we found that ENG significantly induced apoptotic cell death in lung cancer cells through reducing X-linked inhibitor apoptosis (XIAP) expression from the post-translational levels. However, the XIAP ubiquitination was obviously up-regulated by ENG. In addition, second mitochondria-derived activator of caspase (SMAC) expression levels were increased by ENG in lung cancer cells. Notably, SMAC inhibition significantly abrogated ENG-inhibited expression of XIAP. Furthermore, ENG enhanced the interaction between XIAP and SMAC through increasing SMAC secretion from mitochondria to the cytoplasm. Moreover, endoplasmic-reticulum (ER) stress was highly induced by ENG, and we found that inhibiting C/-EBP homologous protein (CHOP), the transcription factor of ER stress, eliminated the regulatory effects of ENG on the expression of SMAC and XIAP. The in vitro analysis showed that ENG treatment caused apparent mitochondrial dysfunction in lung cancer cells. Finally, we showed that ENG effectively reduced the growth of xenograft tumors derived from cell lines with limited toxicity. Taken together, ENG had therapeutic potential against lung cancer progression.
Le texte complet de cet article est disponible en PDF.Abbreviations : Bip, CHOP, COXI, ER, GAPDH, GRP94, IRE1α, MTT, NDUFA9, PERK, PUMA, SDH, SMAC, TUNEL, VDAC, XIAP
Keywords : Lung cancer, Engeletin (ENG), Apoptosis, XIAP and SMAC, ER stress
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