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Quercetin induces protective autophagy and apoptosis through ER stress via the p-STAT3/Bcl-2 axis in ovarian cancer

Abstract

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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Acknowledgements

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.

Author contributions

YL, WG and ZYY contributed equally to this work.

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Correspondence to F. Ye or Q. L. Gao.

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The authors have no conflict of interest.

Additional information

Yi Liu, Wei Gong and Zongyuan Yang contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Figure supplementary 1. pan-caspase rescued the cleavage of Caspase 4 after Qu treatment

. 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)

Figure supplementary 2. All the three branches of ER stress took part in mediating autophagy

. 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)

Figure supplementary 3. Quercetin did not induce ER stress and apoptosis in HOSE cell. (A, B)

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

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Keywords

  • Qu
  • ER stress
  • Autophagy
  • Ovarian cancer
  • p-STAT3/Bcl-2 axis