Abstract
Background
Cucurbitacin-I is a natural cell-permeable triterpenoid compound isolated from Cucurbitaceae and Cruciferae. The pharmacological activity of cucurbitacin-I in human ovarian cancer has been rarely reported.
Objective
The purpose of this study was to investigate the anticancer effect of cucurbitacin-I in SKOV3 human ovarian cancer cells.
Methods
SKOV3 cells were treated with different concentrations of cucurbitacin-I. Cell viability was then measured by CCK-8 assay. Apoptosis, mitochondrial membrane potential, and reactive oxygen species changed by cucurbitacin-I treatment in SKOV3 cells were measured using a Muse Cell Analyzer. Expression levels of various proteins were detected by Western blot analysis.
Results
A decrease in cell viability was observed in SKOV3 cells with cucurbitacin-I treatment. In addition, in SKOV3 cells treated with cucurbitacin-I, a significant increase in apoptosis, increased activity of various caspases, destruction of mitochondrial membrane potential, and generation of reactive oxygen species were observed compared to the control group. At the protein level, an increase in cleaved caspases and Bax/Bcl-2 ratio was induced by cucurbitacin-I treatment in SKOV3 cells. Finally, the levels of phosphorylated human epidermal growth factor receptor 2 (HER2), phosphoinositide 3-kinase (PI3K), AKT serine/threonine kinase 1 (AKT) and forkhead box O3a (FOXO3a) proteins were significantly reduced in cucurbitacin-I treated SKOV3 cells.
Conclusion
Our data demonstrate that cucurbitacin-I induces SKOV-3 cell death by inducing apoptosis via inhibition of HER2 phosphorylation and its downstream signaling molecules including PI3K, AKT and FOXO3a. This suggests a potential therapeutic role of cucurbitacin-I against ovarian cancer.
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Data availability
All data generated or analyzed during this study are available from the corresponding author on reasonable request.
References
Arauna D et al (2019) Natural bioactive compounds as protectors of mitochondrial dysfunction in cardiovascular diseases and aging. Molecules 24(23):4259
Beaufort CM et al (2014) Ovarian cancer cell line panel (OCCP): clinical importance of in vitro morphological subtypes. PLoS ONE 9(9):e103988
Blaskovich MA et al (2003) Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res 63(6):1270–1279
Chakraborty S et al (2023) Through the looking glass: updated insights on ovarian cancer diagnostics. Diagnostics (basel) 13(4):713
Dandawate P et al (2020) Cucurbitacin B and I inhibits colon cancer growth by targeting the Notch signaling pathway. Sci Rep 10(1):1290
Deng C et al (2016) Low nanomolar concentrations of cucurbitacin-I induces G2/M phase arrest and apoptosis by perturbing redox homeostasis in gastric cancer cells in vitro and in vivo. Cell Death Dis 7(2):e2106
Gottlieb E, Armour SM, Harris MH, Thompson CB (2003) Mitochondrial membrane potential regulates matrix configuration and cytochrome c release during apoptosis. Cell Death Differ 10(6):709–717
Han EJ et al (2023) Piperlongumine induces apoptosis and autophagy via the PI3K/Akt/mTOR pathway in KB human cervical cancer cells. Food Chem Toxicol 180:114051
Huang H, Tindall DJ (2007) Dynamic FoxO transcription factors. J Cell Sci 120(15):2479–2487
Iqbal N, Iqbal N (2014) Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Mol Biol Int 2014:852748
Ishdorj G, Johnston JB, Gibson SB (2010) Inhibition of constitutive activation of STAT3 by curcurbitacin-I (JSI-124) sensitized human B-leukemia cells to apoptosis. Mol Cancer Ther 9(12):3302–3314
Jan R, Chaudhry GE (2019) Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv Pharm Bull 9(2):205–218
Jung KW et al (2022) Prediction of cancer incidence and mortality in Korea, 2022. Cancer Res Treat 54(2):345–3451
Kaloni D, Diepstraten ST, Strasser A, Kelly GL (2023) BCL-2 protein family: attractive targets for cancer therapy. Apoptosis 28(1):20–38
Kim HJ, Park JH, Kim JK (2014) Cucurbitacin-I, a natural cell-permeable triterpenoid isolated from Cucurbitaceae, exerts potent anticancer effect in colon cancer. Chem Biol Interact 219:1–8
Li H et al (2019) Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway. J Cell Biochem 120(2):2391–2403
Li R et al (2020) Cucurbitacin I induces apoptosis in ovarian cancer cells through oxidative stress and the p190B-Rac1 signaling axis. Mol Med Rep 22(3):2545–2550
Lin et al (2015) Flavones inhibit breast cancer proliferation through the Akt/FOXO3a signaling pathway. BMC Cancer 15:958
Liu Y et al (2018) Critical role of FOXO3a in carcinogenesis. Mol Cancer 17(1):104
Manoharan S, Prajapati K, Perumal E (2023) Natural bioactive compounds and FOXO3a in cancer therapeutics: an update. Fitoterapia 173:105807
Marrelli M, Statti G, Conforti F (2020) A review of biologically active natural products from mediterranean wild edible plants: benefits in the treatment of obesity and its related disorders. Molecules 25(3):649
Moasser MM (2007) The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26(45):6469–6487
Nakamura H, Takada K (2021) Reactive oxygen species in cancer: current findings and future directions. Cancer Sci 112(10):3945–3952
Niisato N, Marunaka Y (2023) Therapeutic potential of multifunctional myricetin for treatment of type 2 diabetes mellitus. Front Nutr 10:1175660
Pradhan B, Ki JS (2023) Antioxidant and chemotherapeutic efficacies of seaweed-derived phlorotannins in cancer treatment: a review regarding novel anticancer drugs. Phytother Res 37(5):2067–2091
Premkumar DR, Jane EP, Pollack IF (2015) Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells. Cancer Biol Ther 16(2):233–243
Qi J et al (2015) JSI-124 (Cucurbitacin I) inhibits tumor angiogenesis of human breast cancer through reduction of STAT3 phosphorylation. Am J Chin Med 43(2):337–347
Ramalingam P (2016) Morphologic, immunophenotypic, and molecular features of epithelial ovarian cancer. Oncology (williston Park) 30(2):166–176
Ricci JE et al (2004) Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117(6):773–786
Sahoo G, Samal D, Khandayataray P, Murthy MK (2023) A review on caspases: Key regulators of biological activities and apoptosis. Mol Neurobiol 60(10):5805–5837
Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24(10):R453–R462
Shin DW, Bae J, Ha J, Jung KW (2021) Conditional relative survival of ovarian cancer: a korean national cancer registry study. Front Oncol 11:639839
Su Y et al (2008) JSI-124 inhibits glioblastoma multiforme cell proliferation through G(2)/M cell cycle arrest and apoptosis augment. Cancer Biol Ther 7(8):1243–1249
Sung H et al (2021) Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249
Üremiş N et al (2022) Cucurbitacin I exhibits anticancer efficacy through induction of apoptosis and modulation of JAK/STAT3, MAPK/ERK, and AKT/mTOR signaling pathways in HepG2 cell line. J Food Biochem 46(10):e14333
Wang T, Bin Y, Zhao L, Li Q (2023) Positive rate of malignant cells in endometrial cytology samples of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer patients: a systematic review and meta-Analysis. J Cytol 40(2):51–57
Wilken JA, Webster KT, Maihle NJ (2010) Trastuzumab sensitizes ovarian cancer cells to EGFR-targeted therapeutics. J Ovarian Res 3:7
Xu D et al (2022) Cucurbitacin I inhibits the proliferation of pancreatic cancer through the JAK2/STAT3 signalling pathway in vivo and in vitro. J Cancer 13(7):2050–2060
Zeng Y et al (2021) Cucurbitacin IIa: a review of phytochemistry and pharmacology. Phytother Res 35(8):4155–4170
Zhang T et al (2012) Cucurbitacin induces autophagy through mitochondrial ROS production which counteracts to limit caspase-dependent apoptosis. Autophagy 8(4):559–576
Acknowledgements
This research was supported by Daegu Catholic University (2021).
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This work was supported by research grants from Daegu Catholic University in 2021.
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JKK and SWP designed experiments. JWP, SWP and JKK wrote the manuscript. JWP, SMK and SYL performed experiments.
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Ji-Won Park, Seong Mi Kim, Soo Yeon Lee, Seung-Won Park and Jin-Kyung Kim declare no conflict of interest.
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Park, JW., Kim, S.M., Lee, S.Y. et al. Cucurbitacin-I exhibits anticancer activity by inducing apoptosis in SKOV3 human ovarian cancer cells. Mol. Cell. Toxicol. (2024). https://doi.org/10.1007/s13273-024-00451-9
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DOI: https://doi.org/10.1007/s13273-024-00451-9