Quercetin (3,3′,4′,5,7-pentahydroxyflavone, Qu) is a promising cancer chemo-preventive agent for various cancers because it inhibits disease progression and promotes apoptotic cell death. In our previous study, we demonstrated that Qu could evoke ER stress to enhance drug cytotoxicity in ovarian cancer (OC). However, Qu-induced ER stress in OC is still poorly understood. Here, we demonstrated that Qu evoked ER stress to involve in mitochondria apoptosis pathway via the p-STAT3/Bcl-2 axis in OC cell lines and in primary OC cells. Unexpectedly, inhibition of ER stress did not reverse Qu-induced cell death. Further functional studies revealed that Qu-induced ER stress could activate protective autophagy concomitantly by activating the p-STAT3/Bcl-2 axis in this process. Moreover, the autophagy scavenger 3-MA was shown to enhance Qu’s anticancer effects in an ovarian cancer mice xenograft model. These findings revealed a novel role of ER stress as a “double edge sword” participating in Qu-induced apoptosis of OC and might provide a new angle to consider in clinical studies of biological modifiers that may circumvent drug resistance in patients by targeting protective autophagy pathways.
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Grant support: Educational Commission of Hubei Province of China (No. B2016078) National Science Foundation of China (No. 81072135, 81372801, 81272426, 81572570) and the “973” Program of China (No. 2015CB553903) supported this work.
YL, WG and ZYY contributed equally to this work.
Conflict of interest
The authors have no conflict of interest.
Yi Liu, Wei Gong and Zongyuan Yang contributed equally to this work.
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. The effects of pan-caspase on alleviating Qu-induced cleaved caspase-4 were examined by western blot. (A) Lysates were harvested and immunoblotted with Cleaved caspase-4 and GAPDH. (JPG 655 KB)
. The effects of Salubrinal (eIF2-alpha phosphatase inhibitor), 3-E-5,6-D (XBP-1 splicing inhibitor) and sp600125 (JNK inhibitor) on alleviating Qu-induced autophagy were examined by western blot, respectively. (A-C) Lysates were harvested and immunoblotted with Beclin 1 and GAPDH. (TIF 385 KB)
HOSE cell was treated with DMSO (<0.1%), Qu (80 μM) or Qu (80 μM)+3MA for 48 h. (A) Lysates were harvested and immunoblotted with GRP78 and Chop. (B) Annexin V/FITC assay was used to determine the apoptosis rate by flow cytometry. The results were similar in at least three independent experiments. (TIF 651 KB)
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Liu, Y., Gong, W., Yang, Z.Y. et al. Quercetin induces protective autophagy and apoptosis through ER stress via the p-STAT3/Bcl-2 axis in ovarian cancer. Apoptosis 22, 544–557 (2017). https://doi.org/10.1007/s10495-016-1334-2
- ER stress
- Ovarian cancer
- p-STAT3/Bcl-2 axis