Abstract
Echinacoside is a group of natural compounds extracted from medicinal plants Cistanche and Echinacea, which has neuroprotective, antiaging, immunomodulatory and anticancer effects, but its specific role and mechanism in tumor remains partially unclear. To our knowledge, it was the first time to reported the effect of Echinacoside in ovarian cancer. Colony formation, TUNEL staining, Transwell and tube formation assays were conducted to analyze the proliferation, apoptosis, invasion and tube formation abilities of serous ovarian carcinoma cells (SKOV3 and OVCAR-3), respectively. The expressions of apoptosis-, invasion- and PI3K/AKT pathway-related proteins were measured by western blotting. In addition, PI3K agonist (740Y-P) was used to assess the regulatory effect of Echinacoside on PI3K/AKT signaling in ovarian cancer. Finally, the anti-tumor effect of Echinacoside on SKOV3-xenografted mice was evaluated by xenograft tumor mouse model. Our results demonstrated Echinacoside concentration-dependently reduced the proliferation, migration and angiogenesis of ovarian cancer cells, whereas promoted apoptosis. Moreover, western blotting revealed that Echinacoside suppressed the growth of ovarian cancer cells by downregulating the phosphorylation levels of PI3K, AKT and mTOR, which could be partially reversed by 740Y-P. Further, in vivo results showed that Echinacoside could effectively alleviate the tumor growth of xenograft mice, accompanied by the decrease of PI3K/AKT signaling. In general, our results demonstrate that Echinacoside could reduce the ovarian cancer progression through inhibition of PI3K/AKT pathway, suggesting that Echinacoside may be a new treatment option for ovarian cancer.
Similar content being viewed by others
Data availability
All data generated or analyzed during this study are included in this published article.
References
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre JA (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424
Carmeliet P, Jain RK (2011) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discovery 10(6):417–427
Cheaib B, Auguste A, Leary A (2015) The PI3K/Akt/mTOR pathway in ovarian cancer: therapeutic opportunities and challenges. Chin J Cancer 34(1):4–16
Deng M, Zhao JY, Tu PF, Jiang Y, Li ZB, Wang YH (2004) Echinacoside rescues the SHSY5Y neuronal cells from TNFα-induced apoptosis. Eur J Pharmacol 505(1–3):11–18
Dobbin ZC, Landen CN (2013) The importance of the PI3K/AKT/MTOR pathway in the progression of ovarian cancer. Int J Mol Sci 14(4):8213–8227
Dong L, Yu D, Wu N, Wang H, Niu J, Wang Y et al (2015) Echinacoside induces apoptosis in human SW480 colorectal cancer cells by induction of oxidative DNA damages. Int J Mol Sci 16(7):14655–14668
Ferrara N (2001) Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 280(6):1358–1366
Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18(16):1926–1945
Huang J, Zhang L, Greshock J, Colligon TA, Wang Y, Ward R et al (2011) Frequent genetic abnormalities of the PI3K/AKT pathway in primary ovarian cancer predict patient outcome. Genes Chromosom Cancer 50(8):606–618
Huang F, Yao Y, Wu J, Liu Q, Zhang J, Pu X et al (2017) Curcumin inhibits gastric cancer-derived mesenchymal stem cells mediated angiogenesis by regulating NF-κB/VEGF signaling. American Journal of Translational Research 9(12):5538
Huang C, Li H, Feng Y, Li XL et al (2020) Combination therapy with B7H3-redirected bispecific antibody and Sorafenib elicits enhanced synergistic antitumor efficacy. Theranostics 10(23):10498
Imam JS, Plyler JR, Bansal H, Prajapati S, Bansal S, Rebeles J et al (2012) Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization. PLoS ONE 7(12):52397
Isonishi S, Saitou M, Saitou M, Yasuda M, Tanaka T (2007) Differential regulation of the cytotoxicity activity of paclitaxel by orobol and platelet derived growth factor in human ovarian carcinoma cells. Oncol Rep 18(1):195–201
Jiang Y, Tu PF (2009) Analysis of chemical constituents in Cistanche species. J Chromatogr A 1216(11):1970–1979
Jin Y, Feng SJ, Qiu S, Shao N, Zheng JH (2017) LncRNA MALAT1 promotes proliferation and metastasis in epithelial ovarian cancer via the PI3K-AKT pathway. Eur Rev Med Pharmacol Sci 21(14):3176–3184
Kannan K, Coarfa C, Rajapakshe K, Hawkins SM, Matzuk MM, Milosavljevic A et al (2014) CDKN2D-WDFY2 is a cancer-specific fusion gene recurrent in high-grade serous ovarian carcinoma. PLoS Genet 10(3):1004216
Li W, Li Y, Guan S, Fan J, Chen CF, Bright AM et al (2007) Extracellular heat shock protein-90α: linking hypoxia to skin cell motility and wound healing. EMBO J 26(5):1221–1233
Li J, Feng L, Tian C, Tang YL, Tang Y, Hu FQ (2018) Long noncoding RNA-JPX predicts the poor prognosis of ovarian cancer patients and promotes tumor cell proliferation, invasion and migration by the PI3K/Akt/mTOR signaling pathway. Eur Rev Med Pharmacol Sci 22(23):8135–8144
Li X, Hu Z, Shi H, Wang C, Lei J, Cheng Y (2020) Inhibition of VEGFA increases the sensitivity of ovarian cancer cells to chemotherapy by suppressing VEGFA-mediated autophagy. Onco Targets Ther 13(2):8161
Li W, Zhou J, Zhang Y, Zhang J, Li X, Yan Q et al (2021) Echinacoside exerts anti-tumor activity via the miR-503-3p/TGF-β1/Smad aixs in liver cancer. Cancer Cell Int 21(1):1–9
Lugano R, Ramachandran M, Dimberg A (2020) Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 77(9):1745–1770
Ma Y, Zhou G, Li M, Hu DF, Zhang LQ, Liu P et al (2018) Long noncoding RNA DANCR mediates cisplatin resistance in glioma cells via activating AXL/PI3K/Akt/NF-κB signaling pathway. Neurochem Int 118(12):233–241
Ma Q, Zhang J, Zhang M, Lan H et al (2020) MicroRNA-29b targeting of cell division cycle 7-related protein kinase (CDC7) regulated vascular smooth muscle cell (VSMC) proliferation and migration. Ann Transl Med 8(22):1496
Omar A, Kalra RS, Putri J, Elwakeel A, Kaul SC, Wadhwa R (2020) Soyasapogenol-A targets CARF and results in suppression of tumor growth and metastasis in p53 compromised cancer cells. Sci Rep 10(1):1–13
Qiu J, Lin Y, Ye L, Ding J, Feng W, Jin H et al (2014) Overexpression of long non-coding RNA HOTAIR predicts poor patient prognosis and promotes tumor metastasis in epithelial ovarian cancer. Gynecol Oncol 134(1):121–128
Swiatly A, Horala A, Hajduk J, Matysiak J, Markwitz EN, Kokot ZJ (2017) MALDI-TOF-MS analysis in discovery and identification of serum proteomic patterns of ovarian cancer. BMC Cancer 17(1):1–9
Tang C, Gong L, Xu L, Qiu K, Zhang Z, Wan L (2020) Echinacoside inhibits breast cancer cells by suppressing the Wnt/β-catenin signaling pathway. Biochem Biophys Res Commun 526(1):170–175
Wang J, Sun T, Zhao X, Zhang S, Gu Q, Wang X et al (2008) Functional significance of VEGF-a in human ovarian carcinoma: role in vasculogenic mimicry. Cancer Biol Ther 7(5):758–766
Wang S, Zheng G, Tian S, Zhang Y, Shen L, Pak Y et al (2015) Echinacoside improves hematopoietic function in 5-FU-induced myelosuppression mice. Life Sci 123(1):86–92
Wang W, Luo J, Liang Y, Li X (2016) Echinacoside suppresses pancreatic adenocarcinoma cell growth by inducing apoptosis via the mitogen-activated protein kinase pathway. Mol Med Rep 13(3):2613–2618
Wu Y, Li L, Wen T, Li QY (2007) Protective effects of echinacoside on carbon tetrachloride-induced hepatotoxicity in rats. Toxicology 232(12):50–56
Xie H, Zhu H, Cheng C et al (2009) Echinacoside retards cellular senescence of human fibroblastic cells MRC-5. Die Pharm Int J Pharmac Sci 64(11):752–754
Yang X, Fraser M, Abedini MR, Bai T, Tsang BK (2008) Regulation of apoptosis-inducing factor-mediated, cisplatin-induced apoptosis by Akt. Br J Cancer 98(4):803–808
Acknowledgements
Not applicable.
Funding
No funding was received.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval
This present study was performed based on the principles expressed in the Declaration of Helsinki. All animal experiments were approved by the Ethics Committee of the Maternal and Child Healthcare Hospital of Shaanxi Province and conducted in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Liu, J., Tang, N., Liu, N. et al. Echinacoside inhibits the proliferation, migration, invasion and angiogenesis of ovarian cancer cells through PI3K/AKT pathway. J Mol Histol 53, 493–502 (2022). https://doi.org/10.1007/s10735-022-10073-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10735-022-10073-x