GNE-317 suppresses the progression of ovarian cancer by inducing ferroptosis through targeting GPX4

doi:10.21203/rs.3.rs-5035225/v1

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GNE-317 suppresses the progression of ovarian cancer by inducing ferroptosis through targeting GPX4

https://doi.org/10.21203/rs.3.rs-5035225/v1

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Ovarian cancer ranks among prevalent malignancies affecting the female reproductive system with an escalating incidence of drug resistance necessitating intensified efforts in drug discovery research for enhanced patient outcomes. Through rigorous screening within a small molecule compound library, we have pinpointed compound GNE-317 as a robust dual inhibitor targeting PI3K-mTOR via anticancer metabolic library screening methods. Our findings demonstrate that GNE-317 efficaciously impedes ovarian cancer cell proliferation while augmenting cellular demise relative to control groups. Notably, ferroptosis inhibitors exhibit potential in reversing GNE-317-induced cell death without impacting apoptosis or necrosis pathways. Further studies revealed that GNE-317 promoted the accumulation of lipid reactive oxygen species (ROS) and malondialdehyde (MDA). Mechanistically, GNE-317 directly binds to the GPX4, and the GNE-317-mediated increase in lipid ROS and MDA in OC were significantly reversed after GPX4 overexpression in ovarian cancer cells. Thus, GNE-317 can effectively inhibit ovarian cancer development, which may be achieved by increasing GPX4-mediated ferroptosis. These results suggest that GNE-317 has the potential to be a potential drug for targeted treatment of ovarian cancer.

GNE-317

ferroptosis

GPX4

cisplatin

Ovarian cancer (OC) is one of the common malignant tumors of the female reproductive system, and the 5-year survival rate of ovarian cancer is just 30% due to the lack of early screening means, the susceptibility to chemotherapy resistance, and the high recurrence rate [1,2]. Although surgery, chemotherapy, and immunotherapy provide more options for ovarian cancer treatment, but in most cases, it is still difficult for patients to obtain satisfactory treatment results [3, 4]. Therefore, finding a newer, reliable and potent new drug is more meaningful for the treatment and prognosis of ovarian cancer [5, 6].

Ferroptosis was defined in 2012 as a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels[7,8]. In the past few decades, ferroptosis has been proven to engage in human diseases including cancer, neurodegeneration and ischemic disease [9-14]. Ferroptosis is characterized by two major aspects: first, ferroptosis leads to smaller cellular mitochondria and reduced cristae; second, ferroptosis manifests itself as an imbalance in redox homeostasis caused by an abnormal increase in iron-dependent lipid reactive oxygen species(ROS)[15,16].Notably, accumulating evidence shows that ferroptosis plays important roles in the progress of cancer, which highlights its great potential for the treatment of refractory tumors[17]. GNE-317 was identified as dual inhibitors of both PI3K and mTOR that can cross the Blood-Brain Barrier[18]. Co-administration of muMAb 4D5 and GNE-317, a brain-penetrant PI3K/mTOR inhibitor, provided longer survival in mice with brain lesions than either agent alone[19]. GNE-317 was identified markedly inhibited the PI3K pathway in mouse brain, causing high suppression of the pAkt and pS6 signals[18]. In the GS2 model, the GNE-317 average tumor signal appeared lower than in the nontumor region selected whereas the intensity varied by about 4-fold within the tumor[20]. However, whether GNE-317 inhibits the development of ovarian cancer has not been reported.

In this report, we investigated the potent effect of GNE-317 in ovarian cancer cells. We found that GNE-317 effectively inhibits ovarian cancer cell proliferation and increased cell death through inducing the ferroptosis. Interestingly, GNE-317 was able to bind to GPX4 according to molecular docking simulation, which suggested that GPX4 is a potential target of GNE-317. Furthermore, GNE-317 enhanced the sensitivity of the ovarian cancer cells to 5-FU. All the results revealed that GNE-317 was an effective cancer inhibitor.

Identification of GNE-317 reduces ovarian cancer cell proliferation in a dose-dependent manner

To identify small molecular compounds that inhibit ovarian cancer cell, we performed a anti-cancer metabolism library screening in SKOV3 cells and A2780 cells(Fig. 1A). Nine compounds exhibited the most effective compound in inhibiting both SKOV3 cells and A2780 cells according to our screening(Fig.1B).Since GNE-317 was one of the most effective compound among the nine compounds, moreover, GNE-317 has been used in multiple disease such as glioblastoma[21], breast cancer [19], Bladder Cancer[22], and melanoma brain metastasis[23]. It would be interest to repurpose GNE-317 as a ovarian cancer cell inhibitor(the chemical structure was shown in Fig. 1B). Then, we determined the the half-maximal inhibitory concentration (IC₅₀) of GNE-317. As shown in Fig. 1C, the IC₅₀ of GNE-317 was 0.25μM, respectively. In the next experiments, we chose 200nM, 500nM, and 1μM of GNE-317 to treat SKOV3. As shown in Fig 1D, A Cell Counting Kit-8 (CCK-8) proliferative assay demonstrated that GNE-317 dose-dependently decreased SKOV3 cell viability. The PI-FACS assay results showed that GNE-317 disrupted cell cycle progression, causing increased G1-phase cell percentage and decreased S/G2-phase cell percentage (Fig 1E). Moreover, GNE-317 dose-dependently increased the ratio of Trypan blue-positive (“dead”) ovarian cancer cells(Fig 1F).

GNE-317 induces ferroptosis in SKOV3 cells

Next, we analyzed by which way GNE-317 induced SKOV3 cell death.We tested whether GNE-317 could induce apoptosis in human ovarian cancer cells. Following GNE-317 treatment, the percentage of apoptosis cells increased significantly in ovarian cancer cells, indicating apoptosis activation(Fig 2A). Interestingly, GNE-317 treatment selectively enhanced sensitivity to erastin-induced ferroptosis but did not affect actinomycin D-induced autophagy(Fig 2B). Moreover, erastin-induced cell death that is promoted by GNE-317, was significantly blocked by the ferroptosis inhibitor ferrostatin-1, and liproxstatin-1(Fig 2C,D).

Ferroptosis is a distinctive form of regulated cell death that is driven by a lethal accumulation of lipid peroxides in plasma membranes[8].The BODIPY-C11 probe can specifically detect ferroptosis by determining the number of lipid peroxides in cellular membranes. Malondialdehyde (MDA) is the principal and most studied product of polyunsaturated fatty acid peroxidation. Therefore, we next used these compounds to verify if there was an elevation in the production of lipid peroxides and MDA in GNE-317 preincubated cells. The expressions of lipid ROS(Fig 2E) and MDA(Fig 2F) were increased in the GNE-317 treated group compared with the control group. Taken together, these data indicate that the GNE-317 increases cellular lipid peroxidation, and promotes OC cells sensitivity to ferroptosis.

GNE-317 reduces ovarian cancer cell proliferation in a ferroptosis-dependend way

To further elucidate whether the regulation of GNE-317 on ovarian cancer cells exerts its role via its impact on ferroptosis, a ferroptosis inhibitor-ferrostatin-1 was added for further verification. We conducted the verification of the cell function experiment. As depicted in Fig.2A, the addition of the ferrostatin-1 alleviated the retarded cell proliferation induced by GNE-317. After 48 hours of treatment, in comparison with the GNE-317 group, the survival rate of ovarian cancer in the GNE-317 plus ferrostatin-1 group significantly increased, and the mortality rate decreased to a certain extent (Fig.2B,C). The PI-FACS assay also revealed that the addition of the ferrostatin-1 could mitigate the G1 phase retention of ovarian cancer cells induced by GNE-317 (Fig.2D). Meanwhile, we carried out the cell clonal formation experiments. As shown in the Fig.2E, the addition of the ferrostatin-1 restored the decreased cell proliferation induced by GNE-317. The detection of MDA and BODIPY indicated that the ferrostatin-1 could notably restore the ferroptosis of ovarian cancer cells induced by GNE-317 (Fig.2F). JC-1 immunofluorescence staining demonstrated that JC-1 existed as a monomer in the coating plasma after the addition of GNE-317, presenting green fluorescence. The ferrostatin-1 was capable of effectively accumulating more JC-1 in the mitochondrial matrix and forming polymers(Fig.2G). These results indicate that the GNE-317 suppresses OC cells resistance to cell death by selectively enhancing their sensitivity to ferroptosis.

GPX4 is a potential target of GNE-317

Ferroptosis is a form of cell death dependent on ferrous ions and is characterized by the depletion of GSH and the inactivation of glutathione peroxidase 4 (GPX4)[24]. Inactivation of GPX4 ultimately results in overwhelming lipid peroxidation that causes cell death. Here we proposed that GNE-317 might target GPX4. The crystal structure of human GPX4 has been reported (PDB ID: 6HN3), therefore, we performing molecular docking analysis of GNE-317 and GPX4. As shown in Fig. 4A, The figure illustrates the formation of hydrogen bonds between GNE-317 and LYS-48, as well as GLY-47 on GPX4 proteins. These hydrogen bonds contribute to a tight binding of the proteins to small molecules. Furthermore, pi-pi conjugation occurs between TRP-136 on the small molecules and proteins, while hydrophobic interaction with LYS-48 and PRO-155 strengthens van der Waals energy. In this complex, the binding affinity score of GNE-317 and GPX4 was given by the docking software as -6.051 kcal/mol, indicating that GNE-317 was well bound to GPX4 protein. In Fig.4B, GPX4 was significantly down-regulated in malignant tumors of female reproductive system, including OV and UCEC. The strongest positive correlation was observed between the number of CD4⁺T cells, Neutrophil, Macrophage, DC cells and SYTL1 expression(Fig 4C). We further conducted a network analysis of GPX4 by using STRING. In Fig. 4D, the top ten functional partner genes were selected with a high degree of connectivity, including GRSF1, HSPAS, CHAC1, GSR, PRDX6, GSTP1, GSTO1, GSS, HPGDS, and GSTO2 (Table 1). In combination with enrichment analysis via KEGG, we found that they are enriched in the metabolism shown in Fig. Table 2. The analysis above indicated that GPX4 is a potential target of GNE-317.

Overexpression of GPX4 reverses GNE-317-induced ferroptosis and tumor repression in ovarian cancer cells

To further explore the role of GPX4 in GNE-317 regulation of ferroptosis and tumor proliferation, we generated GPX4-overexpression OC cells. Our results showed that GNE-317-mediated inhibition of tumorigenesis were relieved by GPX4 overexpression (Fig 5A, C). In addition, we examined the effect of GNE-317 on cell proliferation by PI-FACS. Compared with the control group, GNE-317 reduced the proliferation of SKOV3, and GPX4 overexpression could reverse this effect (Fig 5 B).The results of the clone formation experiments indicated that GNE-317 effectively suppressed cell proliferation, whereas overexpression of GPX4 abolished its inhibitory effect (Fig5D). Simultaneously, as shown in the Fig 5E, the overexpression of GPX4 notably decreased the JC-1 dimer induced by GNE-317.This result confirms that GPX4 plays a major role in GNE-317-mediated ferroptosis in ovarian cancer cells.

GNE-317 sensitizes OV cells to cisplatin

Chemotherapy is an important part of the standard treatment of ovarian cancer, and commonly used chemotherapy drugs include cisplatin and paclitaxel, but resistance to cisplatin has become increasingly challenging. Since previous studies showed that ferroptosis can be induced by chemotherapy [25, 26], our results also showed that cisplatin induction of cell death can be partially inhibited by the ferroptosis inhibitor ferrostatin-1 (Fig. 6A) and enhanced by the Erastin(Fig. 6B) . As expected, we observed an increase in MDA production and lipid ROS by cisplatin (Fig. 6D,E), indicating that cisplatin can induce ferroptosis in OC cells. Next, we investigated if GNE-317 regulated OC cells sensitivity to cisplatin. The stimulation of GNE-317 increased cisplatin-induced cell death (Fig. 6C). As shown in the Fig 6D,E, the addition of GNE-317 enhanced cisplatin induced ferroptosis in ovarian cancer cells, accompanied by increased MDA production and lipid ROS. In the JC-1 detection experiment, the JC-1 gathered in the mitochondrial matrix to form a polymer, and the polymer emitted strong red fluorescence in control group. After the addition of cisplatin, JC-1 can only exist in the cytoplasm as a monomer and produce green fluorescence, due to the decrease or loss of membrane potential. However, the cells in the GNE-317-cisplatin group exhibited stronger green fluorescence,which indicated that GNE-317 enhanced the ferroptosis of OC cells induced by cisplatin. These data above show that GNE-317-cisplatin combination has potent tumor inhibition capacities in OC.

Specific dual PI3K-mTOR inhibitors exhibit yielded promising results in many cancers. In this study, we have screened and identified that GNE-317, a novel dual PI3K-mTOR inhibitors, efficiently inhibited ovarian cancer cell growth. In SKOV3 ovarian cancer cells , GNE-317 robustly inhibited cell viability, proliferation, while inducing cell cycle arrest. Mechanically, GNE-317 is capable of inducing enhanced iron death in ovarian cancer cells, accompanied by elevated MDA and lipid ROS as well as the formation of JC-1 dimers. The docking analysis showed that GNE-317 could directly bind to GPX4 protein, and the overexpression of GPX4 significantly reversed the tumor inhibition and ferrosposis inhibition induced by GNE-317. Furthermore, GNE-317 enhanced the sensitivity of ovarian cancer cells to cisplaint sensitivity. Our data add a novel dual PI3K-mTOR inhibitor to ovarian cancer therapy and demonstrated the mechanism.

GNE-317 is an understudied dual PI3K-mTOR inhibitor that has been ascribed to have function on many cancer suppressor, but its role in ovarian cancer has not been reported to date. Here we first figure out that GNE-317 can inhibit the proliferation of ovarian cancer cells and cause their retention in G1 phase. At the same time, GNE-317 can enhance the chemotherapy sensitivity of SKOV3 cells to cisplatin. In conclusion, GNE-317 has obvious tumor cell targeting, and is a potential small molecule drug therapeutic target for ovarian cancer.

Ferroptosis describes a form of regulated cell death that occurs as a consequence of lethal lipid peroxidation. Increasing evidence suggests that ferroptosis inducers have anticancer potential[27, 28]. Therefore, exploring effective ferroptosis inducers provides new options for future treatment of ovarian cancer by inducing cellular ferroptosis. GPX4 is an intracellular antioxidant enzyme that inhibits lipid peroxidation in the cell membrane[29]. Here, we found that GNE-317 can bind directly to GPX4, and that overexpression of GPX4 reverses GNE-317-induced ferroposis and tumor suppression. Therefore, we propose that GNE-317 induces ferroposis of ovarian cancer cells through GPX4 to inhibit tumor proliferation.

Cisplatin is a highly effective agent that widely used in the world for treating diverse malignancies, encompassing those affecting the bladder, endometrium, head, kidney, lung, neck, ovary, and testis tumors[30-33]. However, many clinical patients are insensitive to cisplatin. In this study, it was found that GNE-317 can enhance the sensitivity of ovarian cancer cells to cisplatin. The combination of GNE-317 and cisplatin enhances the mortality of ovarian cancer cells and accelerates their retention in G1 phase. In ovarian cancer cell lines, cisplatin is both an inducer of apoptosis and an inducer of ferroptosis. GNE-317 can enhance the induction effect of cisplatin on ferroptosis.

In conclusion, our results discovered the novel dual AKT-mTOR inhibitor which performed an effective role in ovarian cancer cells proliferation and chemotherapy resistance, and advance the mechanistic understanding of GNE-317 control of ovarian cancer cell ferroptosis through GPX4 regulation. Our results reveal GNE-317 as a previously unknown ovarian cancer suppressor and suggest that therapeutic application of GNE-317 in ovarian cancer could improve the efficacy of cancer treatments.

Cell lines

Human ovarian cancer cell line SKOV3 cells were cultured in McCoy’s 5A medium plus 10% FBS and 1% penicillin/streptomycin at 37℃ at 5%CO2 which lines were purchased from Pricella Life Science&Technology Co.,Ltd.

Proliferation Assay

Cellular proliferation ability was detected using a CCK-8 assay.A total of approximately 2000 cells/well were seeded in 96-well plates and then were stimulated with GNE-317 at the 48h, the cellular viability was detected with CCK-8 cultured 30min. Te absorbance was measured at 450 nm with a spectrophotometer (Molecular Devices, San Jose, CA, USA).

Annexin V/PI double staining

Ovarian cancer cells were stimulated with GNE-317 for 48 h, apoptotic cells were identified by the Annexin V-FITC Apoptosis Detection kit (Yeasen, Shanghai, China) in accordance with the manufacturer's instructions. The cell count and percentage were detected by CytoFLEX S Flow Cytometer (Beckman Coulter, California, U.S.). Data acquisition and analysis were performed in Flwojo 10.6

PI-FACS assay

Briefly, cells simulated for 48h were fixed with pre-cooled 75% ethanoland and then stained with propidium iodide (PI, at 10μg/mL) and RNase for 30 min. The FACS assays were carried out to examine cell cycle distribution.

Determination of malondialdehyde (MDA)

Cells were inoculated into 6-well plates and collected after stimulated with GNE-317 or ferrostatin-1 for 48h. The MDA levels were determined using the malondialdehyde (MDA) assay kit (Yeasen, Shanghai, China). The experimental procedures were carried out in strict accordance with the instructions.This assay measures MDA reaction with thiobarbituric acid (TBA) that generate a MDA-TBA adduct in a sample. The MDA-TBA adduct can be quantified colorimetrically (OD =532 nm)

Lipid ROS assay

SKOV3 cells were inoculated at a density of 2x10⁵/cell in 12-well plates at 37°C for 12h and then were sequentially stimulated with GNE-317 or ferrostatin-1 for 48 h. Then C11 BODIPY 581/591 working solution (10μM, MCE, USA) was added, and incubated at 37°C for 30min. The cells were then collected by trypsin without EDTA and washed twice with PBS followed by resuspension in 500μl PBS. ROS levels were analyzed using a CytoFLEX cytometer instrument (Beckman Coulter), and the data were analyzed by Flwojo 10.6

Colony formation

For colony formation assays, the cells (500 cells/well) were seeded in a six-

well plate and incubated for 2 weeks until the appearance of cell colonies, which were fixed with methanol and stained with Giemsa.

Molecular docking

The crystal structure of GPX4 protein used for the connection was downloaded from the PDB database, the PDB ID of GPX4 was 6hn3, and the 3D structure of small molecule GNE-317 was downloaded from the PUBCHEM database, and the energy was minimized under the MMFF94 force field. In this study, AutoDock Vina 1.2.3 software 1 was used to perform molecular docking work. Before docking, PyMol 2.5.52 was used to treat receptor proteins, including removing water molecules, salt ions and small molecules. The docking box is then set up to enclose the entire protein structure. In addition, ADFRsuite 1.03 is used to convert all processed small molecules and receptor proteins into the PDBQT format required for AutoDock Vina 1.2.3 docking. For interconnection, set the global search detail to 32 and retain the default Settings for other parameters. The docking conformation with the highest output score was considered to be the associative conformation. Finally, PyMol 2.5.5 docking results were used for visual analysis.

Statistical Analysis

Data were analyzed with GraphPad Prism 8. T-tests was used to compare differences between columns. Data are presented as mean±standard deviation (SD). All experiments were performed in at least triplicate. Statistical significance was defined as p < 0.05. *p < 0.05, **p < 0.01.

Acknowledgement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

Lekai Nie and Peihai Zhang formulated the study concept, designed the studies, and performed the experiments. Xiaoning Liu and Lei Cheng analyzed the results.

Declaration of Interests

The authors declare no competing interests.

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Tables are available in the Supplementary Files section.

No competing interests reported.

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Table 1
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Table 2

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GNE-317 suppresses the progression of ovarian cancer by inducing ferroptosis through targeting GPX4

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