Paeonol induces cytoprotective autophagy via blocking the Akt/mTOR pathway in ovarian cancer cells

BackgroundThe phosphoinositide 3 kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is frequently aberrantly activated in ovarian cancer and confers the chemoresistant phenotype of ovarian cancer cells. LY294002 (PI3K inhibitor) and metformin (5′-adenosine monophosphate [AMP]-activated protein kinase [AMPK] activator) are 2 drugs that were known to inhibit mTOR expression through the AKT-dependent and AKT-independent pathways, respectively. In this study, we explored the effectiveness of LY294002 and metformin in combination on inhibition of ovarian cancer cell growth.MethodsWestern blotting was used to detect the changes of PI3K/AKT/mTOR and AMPK/acetyl-CoA carboxylase (ACC) signaling activities, cell cycle control, and apoptosis. Cell growth was evaluated by cell proliferation, colony formation, and soft agar assays. Flow cytometry was used to study cell cycle distribution and cell death upon drug treatment.ResultsOur study showed that LY294002 and metformin in combination could simultaneously enhance the repression of the PI3K/AKT/mTOR pathway and the activation of the AMPK/ACC pathway. The downstream target of AKT and AMPK, mTOR, was cooperatively repressed when the drugs were used together. The cell cycle regulatory factors, p53, p27, and p21, were up-regulated. On the other hand, caspase 3 and poly (ADP-ribose) polymerase activities involved in apoptosis were also activated. Cell growth assays indicated that LY294002 and metformin could effectively inhibit ovarian cancer cell growth. Flow cytometry analysis showed that the treatment of the 2 drugs mentioned above induced cell cycle arrest at G1 phase and increased sub-G1 apoptotic cells.ConclusionThe combinational use of LY294002 and metformin can enhance inhibition of the growth and induction of the apoptosis of ovarian cancer cells. Our results may provide significant insight into the future therapeutic regimens in ovarian cancer.

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A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

International Journal of Biological Sciences ◽

10.7150/ijbs.44343 ◽

2020 ◽

Vol 16 (11) ◽

pp. 1901-1916 ◽

Cited By ~ 3

Author(s):

In Hwan Tae ◽

Ji Yeon Son ◽

Su Hyun Lee ◽

Mi-Young Ahn ◽

Kyungsil Yoon ◽

...

Keyword(s):

Ovarian Cancer ◽

Energy Metabolism ◽

Cancer Cells ◽

Mtor Pathway ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Sirt1 Inhibitor

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Combination of metformin and RG7388 enhances inhibition of growth and induction of apoptosis of ovarian cancer cells through the PI3K/AKT/mTOR pathway

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2020.09.135 ◽

2020 ◽

Vol 533 (4) ◽

pp. 665-671

Author(s):

Yingying Cui ◽

Jing Zhou ◽

Fengnian Rong

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Mtor Pathway ◽

Ovarian Cancer Cells ◽

Inhibition Of Growth ◽

Induction Of Apoptosis

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Inhibiting the mTOR Pathway Synergistically Enhances Cytotoxicity in Ovarian Cancer Cells Induced by Etoposide through Upregulation of c-Jun

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-11-0190 ◽

2011 ◽

Vol 17 (14) ◽

pp. 4742-4750 ◽

Cited By ~ 19

Author(s):

Hiroaki Itamochi ◽

Tetsuro Oishi ◽

Muneaki Shimada ◽

Shinya Sato ◽

Kazunori Uegaki ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Mtor Pathway ◽

Ovarian Cancer Cells

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Guizhi Fuling Wan, a Traditional Chinese Herbal Formula, Sensitizes Cisplatin-Resistant Human Ovarian Cancer Cells through Inactivation of the PI3K/AKT/mTOR Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/4651949 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Li Han ◽

Xiaojuan Guo ◽

Hua Bian ◽

Lei Yang ◽

Zhong Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Mtor Pathway ◽

Cell Counting ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Bioactive Constituents ◽

Anticancer Efficacy ◽

Protein Levels ◽

And Function

The aim of the study was to explore the possible mechanisms that Guizhi Fuling Wan (GFW) enhances the sensitivity of the SKOV3/DDP ovarian cancer cells and the resistant xenograft tumours to cisplatin. Rat medicated sera containing GFW were prepared by administering GFW to rats, and the primary bioactive constituents of the sera were gallic acid, paeonol, and paeoniflorin analysed by HPLC/QqQ MS. Cell counting kit-8 analysis was shown that coincubation of the sera with cisplatin/paclitaxel enhanced significantly the cytotoxic effect of cisplatin or paclitaxel in SKOV3/DDP cells. The presence of the rat medicated sera containing GFW resulted in an increase in rhodamine 123 accumulation by flow cytometric assays and a decrease in the protein levels of P-gp, phosphorylation of AKT at Ser473, and mTOR in a dose-dependent manner in SKOV3/DDP cells by western blot analysis, but the sera had no effect on the protein levels of PI3K p110αand total AKT. The low dose of GFW enhanced the anticancer efficacy of cisplatin and paclitaxel treatment in resistant SKOV3/DDP xenograft tumours. GFW could sensitize cisplatin-resistant SKOV3/DDP cells by inhibiting the protein level and function of P-gp, which may be medicated through inactivation of the PI3K/AKT/mTOR pathway.

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PTPRZ1 Inhibits the Cisplatin Resistance of Ovarian Cancer by Regulating PI3K/AKT/mTOR Signal Pathway

10.21203/rs.3.rs-57236/v1 ◽

2020 ◽

Author(s):

Peng Wang ◽

Yuanjing Hu ◽

Pengpeng Qu ◽

Ying Zhao ◽

Jing Liu ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cisplatin Resistance ◽

Biological Effects ◽

Mtor Pathway ◽

Ovarian Cancer Cells ◽

Tumor Resistance ◽

Normal Tissues ◽

Qrt Pcr ◽

Cancer Tissues

Abstract Background: Cisplatin resistance (DDP resistance) is a major cause for poor prognosis of ovarian cancer patients. PTPRZ1 has been proven to participate in the occurrence and development of multiple tumors, including tumor resistance. This study was designed to investigate the roles of PTPRZ1 in DDP-resistant ovarian cancer cells and their possible mechanism.Methods: PTPRZ1 expression in ovarian cancer tissues and normal tissues was analyzed by GEPIA database and verified by qRT-PCR. PTPRZ1 expression in normal ovarian cancer cells and DDP-resistant ovarian cancer cells was also analyzed. Subsequently, qRT-PCR, western blot, MTT experiment and flow cytometry were used to assess the effects of PTPRZ1-PI3K/AKT/mTOR regulating axis on cisplatin resistance of ovarian cancer.Results: PTPRZ1 expression was abnormally low in ovarian cancer tissues, and notably reduced in DDP-resistant ovarian cancer cells. MTT experiment and flow cytometer indicated that overexpression of PTPRZ1 enhanced the cisplatin sensitivity of ovarian cancer cells and promoted the cell apoptosis. The results of mechanism research showed that PTPRZ1 exerted its biological effects possibly through blocking PI3K/AKT/mTOR pathway.Conclusion: PTPRZ1 suppresses the cisplatin resistance of ovarian cancer and induces the cytotoxicity by blocking PI3K/AKT/mTOR pathway.

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GALNT14 regulates ferroptosis and apoptosis of ovarian cancer through the EGFR/mTOR pathway

Future Oncology ◽

10.2217/fon-2021-0883 ◽

2021 ◽

Author(s):

Hua-wen Li ◽

Mu-biao Liu ◽

Xue Jiang ◽

Ting Song ◽

Shu-xian Feng ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Death ◽

Cancer Cells ◽

Western Blotting ◽

Mtor Inhibitor ◽

Cell Function ◽

Cisplatin Resistance ◽

Mtor Pathway ◽

Ovarian Cancer Cells ◽

Western Blotting Assay

Background: Chemoresistance usually occurs in ovarian cancer. We aimed to explore the mechanisms of chemoresistance. Methods: Western blotting assay was used to detect the expression of GALNT14. Further cell function experiments were performed to investigate the effect of GALNT14 in ovarian cancer. Results: GALNT14 is significantly upregulated in ovarian cancer. Downregulation of GALNT14 significantly inhibits both apoptosis and ferroptosis of ovarian cancer cells. A further mechanism assay illustrated that downregulation of GALNT14 suppresses the activity of the mTOR pathway through modifying O-glycosylation of EGFR. Finally, an additive effect promoting cell death occurs with a combination of an mTOR inhibitor and cisplatin. Conclusion: Our study might provide a promising method to overcome cisplatin resistance for patients with ovarian cancer.

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