Cucurbitacin I induces apoptosis in ovarian cancer cells through oxidative stress and the p190B‑Rac1 signaling axis

Li,Ruli; Xiao,Jianbo; Tang,Sufan; Lin,Xinjing; Xu,Honglin; Han,Bin; Yang,Ming; Liu,Fu

doi:10.3892/mmr.2020.11327

Cucurbitacin I induces apoptosis in ovarian cancer cells through oxidative stress and the p190B‑Rac1 signaling axis

Authors:
- Ruli Li
- Jianbo Xiao
- Sufan Tang
- Xinjing Lin
- Honglin Xu
- Bin Han
- Ming Yang
- Fu Liu
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Affiliations: Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China, Department of Medical Imaging, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China, School of Pharmacy, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
Published online on: July 10, 2020 https://doi.org/10.3892/mmr.2020.11327
Pages: 2545-2550

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Abstract

Ovarian cancer is a serious threat to women's life and health, with a high mortality rate. Therefore, in addition to improving surgery for ovarian cancer, it is particularly important to develop novel drug treatments. In the present study, the anticancer effects of cucurbitacin I, a natural product, were investigated. Cucurbitacin I impaired the viability of SKVO3 cells in a concentration‑ and time‑dependent manner. Apoptosis was involved in the process of cucurbitacin I‑induced cell death, with an increase observed in cleaved‑caspase 3 and BAX, and a decrease in Bcl‑2. Cucurbitacin I caused a notable increase in intracellular reactive oxygen species, and regulated Kelch‑like ECH‑associated protein 1 and nuclear factor erythroid‑derived 2‑like 2 to decrease the expression of antioxidant‑related genes. In addition, Cucurbitacin I induced cell shrinkage by regulating the p190BRhoGAP (p190B)‑Rac1 signaling axis related to the cytoskeleton. In brief, these results suggested that cucurbitacin I induced cell death through oxidative stress and the p190B‑Rac1 signaling axis in SKVO3 cells. The results may provide novel evidence for the treatment of ovarian cancer.

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1	Hunn J and Rodriguez GC: Ovarian cancer: Etiology, risk factors, and epidemiology. Clin Obstet Gynecol. 55:3–23. 2012. View Article : Google Scholar : PubMed/NCBI
2	Farsinejad S, Cattabiani T, Muranen T and Iwanicki M: Ovarian cancer dissemination-A cell Biologist's perspective. Cancers (Basel). 11:19572019. View Article : Google Scholar
3	Yeung TL, Leung CS, Yip KP, Au Yeung CL, Wong ST and Mok SC: Cellular and molecular processes in ovarian cancer metastasis. A review in the theme: Cell and molecular processes in cancer metastasis. Am J Physiol Cell Physiol. 309:C444–C456. 2015. View Article : Google Scholar : PubMed/NCBI
4	Moufarrij S, Dandapani M, Arthofer E, Gomez S, Srivastava A, Lopez-Acevedo M, Villagra A and Chiappinelli KB: Epigenetic therapy for ovarian cancer: Promise and progress. Clin Epigenetics. 11:72019. View Article : Google Scholar : PubMed/NCBI
5	Xu K, Xiao J, Zheng K, Feng X, Zhang J, Song D, Wang C, Shen X, Zhao X, Wei C, et al: miR-21/STAT3 signal is involved in odontoblast differentiation of human dental pulp stem cells mediated by TNF-α. Cell Reprogram. 20:107–116. 2018. View Article : Google Scholar : PubMed/NCBI
6	Ni Y, Wu S, Wang X, Zhu G, Chen X, Ding Y and Jiang W: Cucurbitacin I induces pro-death autophagy in A549 cells via the ERK-mTOR-STAT3 signaling pathway. J Cell Biochem. 119:6104–6112. 2018. View Article : Google Scholar : PubMed/NCBI
7	Zhu X, Huang H, Zhang J, Liu H, Ao R, Xiao M and Wu Y: The anticancer effects of Cucurbitacin I inhibited cell growth of human non-small cell lung cancer through PI3K/AKT/p70S6K pathway. Mol Med Rep. 17:2750–2756. 2018.PubMed/NCBI
8	Yang Q, Qiu H, Xie H, Qi Y, Cha H, Qu J, Wang M, Feng Y, Ye X, Mu J and Huang J: A Schistosoma japonicum infection promotes the expansion of Myeloid-derived suppressor cells by activating the JAK/STAT3 pathway. J Immunol. 198:4716–4727. 2017. View Article : Google Scholar : PubMed/NCBI
9	Nguyen BC, Taira N, Maruta H and Tawata S: Artepillin C and other Herbal PAK1-blockers: Effects on hair cell proliferation and related PAK1-dependent biological function in cell culture. Phytother Res. 30:120–127. 2016. View Article : Google Scholar : PubMed/NCBI
10	Moloney JN and Cotter TG: ROS signalling in the biology of cancer. Semin Cell Dev Biol. 80:50–64. 2018. View Article : Google Scholar : PubMed/NCBI
11	Zhang Y, Yan T, Sun D, Xie C, Wang T, Liu X, Wang J, Wang Q, Luo Y, Wang P, et al: Rutaecarpine inhibits KEAP1-NRF2 interaction to activate NRF2 and ameliorate dextran sulfate sodium-induced colitis. Free Radic Biol Med. 148:33–41. 2020. View Article : Google Scholar : PubMed/NCBI
12	Wang J, Zhang W, Lv C, Wang Y, Ma B, Zhang H, Fan Z, Li M and Li X: A novel biscoumarin compound ameliorates cerebral ischemia reperfusion-induced mitochondrial oxidative injury via Nrf2/Keap-1/ARE signaling. Neuropharmacology. 167:1079182020. View Article : Google Scholar : PubMed/NCBI
13	Tian T, Chen ZH, Zheng Z, Liu Y, Zhao Q, Liu Y, Qiu H, Long Q, Chen M, Li L, et al: Investigation of the role and mechanism of ARHGAP5-mediated colorectal cancer metastasis. Theranostics. 10:5998–6010. 2020. View Article : Google Scholar : PubMed/NCBI
14	Héraud C, Pinault M, Lagrée V and Moreau V: p190RhoGAPs, the ARHGAP35- and ARHGAP5-encoded proteins, in health and disease. Cells. 8:3512019. View Article : Google Scholar
15	Frank SR, Köllmann CP, Luong P, Galli GG, Zou L, Bernards A, Getz G, Calogero RA, Frödin M and Hansen SH: p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity. J Cell Biol. 217:3183–3201. 2018. View Article : Google Scholar : PubMed/NCBI
16	Bustos RI, Forget MA, Settleman JE and Hansen SH: Coordination of Rho and Rac GTPase function via p190B RhoGAP. Curr Biol. 18:1606–1611. 2008. View Article : Google Scholar : PubMed/NCBI
17	Hwang M, Peddibhotla S, McHenry P, Chang P, Yochum Z, Park KU, Sears JC and Vargo-Gogola T: P190B RhoGAP regulates chromosome segregation in cancer cells. Cancers (Basel). 4:475–489. 2012. View Article : Google Scholar : PubMed/NCBI
18	Heckman-Stoddard BM, Vargo-Gogola T, McHenry PR, Jiang V, Herrick MP, Hilsenbeck SG, Settleman J and Rosen JM: Haploinsufficiency for p190B RhoGAP inhibits MMTV-Neu tumor progression. Breast Cancer Res. 11:R612009. View Article : Google Scholar : PubMed/NCBI
19	Zhai KF, Duan H, Cui CY, Cao YY, Si JL, Yang HJ, Wang YC, Cao WG, Gao GZ and Wei ZJ: Liquiritin from Glycyrrhiza uralensis attenuating rheumatoid arthritis via reducing inflammation, suppressing angiogenesis, and inhibiting MAPK signaling pathway. J Agric Food Chem. 67:2856–2864. 2019. View Article : Google Scholar : PubMed/NCBI
20	Wang H and Joseph JA: Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radic Biol Med. 27:612–616. 1999. View Article : Google Scholar : PubMed/NCBI
21	Zhai KF, Zheng JR, Tang YM, Li F, Lv YN, Zhang YY, Gao Z, Qi J, Yu BY and Kou JP: The Saponin D39 blocks dissociation of non-muscular myosin heavy chain IIA from TNF receptor 2, suppressing tissue factor expression and venous thrombosis. Br J Pharmacol. 174:2818–2831. 2017. View Article : Google Scholar : PubMed/NCBI
22	Li RL, Wu SS, Wu Y, Wang XX, Chen HY, Xin JJ, Li H, Lan J, Xue KY, Li X, et al: Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent activation of the AMPK-ULK1 pathway. J Mol Cell Cardiol. 121:242–255. 2018. View Article : Google Scholar : PubMed/NCBI
23	Earp M, Tyrer JP, Winham SJ, Lin HY, Chornokur G, Dennis J, Aben KKH, Anton-Culver H, Antonenkova N, Bandera EV, et al: Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility. PLoS One. 13:e01975612018. View Article : Google Scholar : PubMed/NCBI
24	Zhang T, Li Y, Park KA, Byun HS, Won M, Jeon J, Lee Y, Seok JH, Choi SW, Lee SH, et al: Cucurbitacin induces autophagy through mitochondrial ROS production which counteracts to limit caspase-dependent apoptosis. Autophagy. 8:559–576. 2012. View Article : Google Scholar : PubMed/NCBI
25	Dietz A, Dalda N, Zielke S, Dittmann J, van Wijk SJL, Vogler M and Fulda S: Proteasome inhibitors and Smac mimetics cooperate to induce cell death in diffuse large B-cell Lymphoma by stabilizing NOXA and triggering mitochondrial apoptosis. Int J Cancer. 4:9822020.
26	Malinina A, Dikeman D, Westbrook R, Moats M, Gidner S, Poonyagariyagorn H, Walston J and Neptune ER: IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung. Aging Cell. 19:e131302020. View Article : Google Scholar : PubMed/NCBI
27	Zhai KF, Duan H, Chen Y, Khan GJ, Cao WG, Gao GZ, Shan LL and Wei ZJ: Apoptosis effects of imperatorin on synoviocytes in rheumatoid arthritis through mitochondrial/caspase-mediated pathways. Food Funct. 9:2070–2079. 2018. View Article : Google Scholar : PubMed/NCBI
28	Ma M, Wang X, Liu N, Shan F and Feng Y: Low-dose naltrexone inhibits colorectal cancer progression and promotes apoptosis by increasing M1-type macrophages and activating the Bax/Bcl-2/caspase-3/PARP pathway. Int Immunopharmacol. 83:1063882020. View Article : Google Scholar : PubMed/NCBI
29	Aggarwal V, Tuli HS, Varol A, Thakral F, Yerer MB, Sak K, Varol M, Jain A, Khan MA and Sethi G: Role of reactive oxygen species in cancer progression: Molecular mechanisms and recent advancements. Biomolecules. 9:7352019. View Article : Google Scholar
30	Li H, Chen H, Li R, Xin J, Wu S, Lan J, Xue K, Li X, Zuo C, Jiang W and Zhu L: Cucurbitacin I induces cancer cell death through the endoplasmic reticulum stress pathway. J Cell Biochem. Sep 11–2018.(Epub ahead of print).