2. Academic Validation
  3. Mechanisms of autophagy and endoplasmic reticulum stress in the reversal of platinum resistance of epithelial ovarian cancer cells by naringin

Mechanisms of autophagy and endoplasmic reticulum stress in the reversal of platinum resistance of epithelial ovarian cancer cells by naringin

  • Mol Biol Rep. 2023 Jun 16. doi: 10.1007/s11033-023-08558-3.
Jun Zhu 1 2 3,  Shixin Lin 1 2 3,  Xia Zou 4,  Xintong Chen 4,  Yanlan Liu 1,  Xiaorong Yang 4,  Jun Gao # 5 6,  Hong Zhu # 7
Affiliations

Affiliations

  • 1 The Third Affiliated Hospital of Nanchang University, The First Hospital of Nanchang City, Nanchang, Jiangxi, China.
  • 2 Jiangxi Provincial Key Laboratory of Tumor Metastasis and Precision Therapy, Nanchang, Jiangxi, China.
  • 3 Nanchang Key Laboratory of Precision Therapy for Gynecological Neoplasms, Nanchang, Jiangxi, China.
  • 4 Department of Gynecologic Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China.
  • 5 Department of Gynecologic Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China. drgaojun@yeah.net.
  • 6 Nanchang Key Laboratory of Precision Therapy for Gynecological Neoplasms, Nanchang, Jiangxi, China. drgaojun@yeah.net.
  • 7 Department of Gynecologic Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China. 24zhuhong@163.com.
  • # Contributed equally.
PMID: 37326754 DOI: 10.1007/s11033-023-08558-3
Abstract

Objective: Our previous studies showed that naringin (Nar) can effectively reverse the cisplatin resistance of ovarian Cancer cells. This study aims to explore the potential mechanism by which Nar reverses cisplatin resistance in ovarian Cancer.

Methods: The proliferative activity of cells was evaluated using CCK8 and cell clone formation assays. Autophagic flux in cells was evaluated via LC3B immunofluorescence and monodansylcadaverine (MDC) staining. The expression levels of Autophagy, endoplasmic reticulum (ER) stress, and apoptosis-related proteins were detected via Western blotting. Autophagy and ER stress were regulated using siATG5, siLC3B, rapamycin (Rap), chloroquine (CQ), 4-phenylbutyric acid (4-PBA), and thapsigargin (TG). siATG5 and siLC3B are short interfering RNAs (siRNAs) used to knock down the expression of ATG5 and LC3B genes, respectively.

Results: Nar inhibited Autophagy in SKOV3/DDP cells by activating the PI3K/Akt/mTOR pathway. And Nar increased the levels of ER stress-related proteins, namely, P-PERK, GRP78, and CHOP, and promoted Apoptosis in SKOV3/DDP cells. Moreover, treatment with the inhibitor of ER stress alleviated Apoptosis induced by Nar in SKOV3/DDP cells. In addition, compared to cisplatin or naringin alone, the combination of Nar and cisplatin significantly reduced the proliferative activity of SKOV3/DDP cells. And siATG5, siLC3B, CQ or TG pretreatment further inhibited the proliferative activity of SKOV3/DDP cells. Conversely, Rap or 4-PBA pretreatment alleviated the cell proliferation inhibition caused by Nar combined with cisplatin.

Conclusion: Nar not only inhibited the Autophagy in SKOV3/DDP cells by regulating the PI3K/Akt/mTOR signalling pathway, but also promoted Apoptosis in SKOV3/DDP cells by targeting ER stress. Nar can reverse the cisplatin resistance in SKOV3/DDP cells through these two mechanisms.

Keywords

Autophagy; Cisplatin-resistant ovarian cancer; Endoplasmic reticulum stress; Naringin.

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