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

• Published in: Apoptosis (London) Vol. 22; no. 4; pp. 544 - 557
• Main Authors: Liu, Y., Gong, W., Yang, Z. Y., Zhou, X. S., Gong, C., Zhang, T. R., Wei, X., Ma, D., Ye, F., Gao, Q. L.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2017; Springer; Springer Nature B.V
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Autophagy - drug effects; Autophagy - physiology; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Cell Biology; Cell Line, Tumor; Chemotherapy; Cytotoxicity; Development and progression; Drug resistance; Endoplasmic Reticulum Stress - drug effects; Ethylenediaminetetraacetic acid; Female; Humans; Medical research; Medicine, Experimental; Mice; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Neoplasm Proteins - physiology; Oncology; Original Paper; Ovarian cancer; Ovarian Neoplasms - pathology; Quercetin - pharmacology; Quercetin - therapeutic use; Random Allocation; RNA, Small Interfering - genetics; Signal Transduction - drug effects; Signal Transduction - physiology; Specific Pathogen-Free Organisms; STAT3 Transcription Factor - physiology; Taurochenodeoxycholic Acid - pharmacology; Tumor Stem Cell Assay; Virology; Xenograft Model Antitumor Assays; ER stress; Qu; Autophagy; p-STAT3/Bcl-2 axis; Ovarian cancer
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-016-1334-2

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.