Tumor Biology

, Volume 37, Issue 8, pp 11007–11015 | Cite as

Blockage of glutaminolysis enhances the sensitivity of ovarian cancer cells to PI3K/mTOR inhibition involvement of STAT3 signaling

  • Lili Guo
  • Bo Zhou
  • Zhengqing Liu
  • Ying Xu
  • Hao Lu
  • Meng Xia
  • Ensong Guo
  • Wanying Shan
  • Gang Chen
  • Changyu WangEmail author
Original Article


The PI3K/Akt/mTOR axis in ovarian cancer is frequently activated and implicated in tumorigenesis. Specific targeting of this pathway is therefore an attractive therapeutic approach for ovarian cancer. However, ovarian cancer cells are resistant to PP242, a dual inhibitor of mTORC1 and mTORC2. Interestingly, blockage of GLS1 with a selective inhibitor, CB839, or siRNA dramatically sensitized the PP242-induced cell death, as evident from increased PARP cleavage. The anti-cancer activity of CB-839 and PP242 was abrogated by the addition of the TCA cycle product α-ketoglutarate, indicating the critical function of GLS1 in ovarian cancer cell survival. Finally, glutaminolysis inhibition activated apoptosis and synergistically sensitized ovarian cancer cells to priming with the mTOR inhibitor PP242. GLS1 inhibition significantly reduced phosphorylated STAT3 expression in ovarian cancer cells. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy to overcome resistance to PI3K/Akt/mTOR inhibition.


Glutaminase1 GLS1 Metabolic reprogramming Ovarian cancer Drug resistance 



We thank all the people who participate in the study.

Compliance with ethical standards

Grant support

National Science Foundation of China (no. 30943187.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest


Supplementary material

13277_2016_4984_Fig5_ESM.jpg (130 kb)
Fig. S1

Effect of PP242 on C13K and SKOV3 cells (TIFF). (A). The cells were incubated with PP242 (0 μM to 80 μM) for 48 h and subjected to an CCK8 assay to determine the cell viability. (B) mRNA levels of enzymes involved in glutaminolysis and glycolysis that were targeted in SKOV3 cell. Cells were treated with 1 μ M PP242, or control DMSO for 48 h. Data represent the mean ± SEM of three independent experiments. (C.D) C13K and SKOV3 Cell death were evaluated via flow cytometry after Annexin V and PI staining. As a positive control, C13K and SKOV3 cells were treated with 40 um cisplatin for 48 h. (JPG 130 kb)

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High Resolution Image (TIF 45588 kb)
13277_2016_4984_Fig6_ESM.jpg (95 kb)
Fig. S2

GLS1 knockdown potentiated the effect of PP242 cytotoxicity in C13K cells (TIFF). C13K cells were transfected with GLS1siRNA for 24 h, followed by treatment with 1 u M PP242 for 48 h. Cell death was evaluated via flow cytometry after Annexin V and PI staining. (JPG 95 kb)

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High Resolution Image (TIF 42690 kb)
13277_2016_4984_Fig7_ESM.jpg (117 kb)
Fig. S3

Combination treatment with a GLS1 inhibitor and PP242 induces cell death (TIFF). (A.B) The cells were incubated with PP242/CB839 (0 μM to 40 μM) alone or co-treatment for 48 h and subjected to an CCK8 assay to determine the cell viability. (C.D). C13K and SKOV3 Cell death was evaluated by flow cytometry after Annexin V and PI staining. (JPG 116 kb)

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High Resolution Image (TIF 41000 kb)
13277_2016_4984_Fig8_ESM.jpg (188 kb)
Fig. S4

GLS1 promotes cancer cell survival in the way of α-KG (intermediate for TCA). The metabolite dm-αKG (10 mM) was tested for the ability to rescue the viability in C13K cells treated with both 1 μ M PP242 and 1 μ M CB839 for 2 days. Cell death was evaluated by flow cytometry after Annexin V and PI staining. (JPG 188 kb)

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13277_2016_4984_MOESM5_ESM.docx (16 kb)
Table S1 (DOCX 16 kb)
13277_2016_4984_MOESM6_ESM.docx (16 kb)
Table S2 (DOCX 15 kb)
13277_2016_4984_MOESM7_ESM.docx (16 kb)
Table S3 (DOCX 16 kb)


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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Lili Guo
    • 1
    • 2
  • Bo Zhou
    • 1
  • Zhengqing Liu
    • 3
  • Ying Xu
    • 1
  • Hao Lu
    • 1
  • Meng Xia
    • 1
  • Ensong Guo
    • 1
  • Wanying Shan
    • 1
  • Gang Chen
    • 1
  • Changyu Wang
    • 1
    Email author
  1. 1.Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Department of Obstetrics and Gynecology, Taihe HospitalHubei University of MedicineShiyan CityChina
  3. 3.Department of Intensive Care Unit, Taihe HospitalHubei University of MedicineShiyan CityChina

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