Tubeimoside‑1 induces apoptosis in human glioma U251 cells by suppressing PI3K/Akt‑mediated signaling pathways

Cao,Li‑Juan; Xie,Hai‑Tang; Chu,Zhong‑Xia; Ma,Yue; Wang,Ming‑Ming; Shi,Zhuang

doi:10.3892/mmr.2020.11224

Tubeimoside‑1 induces apoptosis in human glioma U251 cells by suppressing PI3K/Akt‑mediated signaling pathways

Authors:
- Li‑Juan Cao
- Hai‑Tang Xie
- Zhong‑Xia Chu
- Yue Ma
- Ming‑Ming Wang
- Zhuang Shi
View Affiliations

Affiliations: Department of Pediatrics, Affiliated Hospital of Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia Autonomous Region 028007, P.R. China, Department of Mongolian Medicine Hand Foot Surgery, Affiliated Hospital of Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia Autonomous Region 028007, P.R. China
Published online on: June 11, 2020 https://doi.org/10.3892/mmr.2020.11224
Pages: 1527-1535
Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Tubeimoside-1 (TBMS1), a traditional Chinese herb extracted from Bolbostemma paniculatum (Maxim.), induces apoptosis in a number of human cancer cell lines. TBMS1 has been reported to induce apoptosis in human glioma cells, however the mechanism remains to be elucidated. The present study explored TBMS1‑induced PI3K/Akt‑related pathways in human glioma cells. The human glioma U251 and the human astrocyte (HA) cell lines were treated with various concentrations of TBMS1. MTT assays were conducted to analyze cell viability. Cell cycle distribution and the rate of apoptosis were assessed using flow cytometry. BrdU incorporation and Hoechst 33342 staining were performed to analyze the cell cycle and apoptosis, respectively. Western blotting was performed to investigate protein expression levels. The results demonstrated that TBMS1 reduced cell viability in human glioma cells U251 by suppressing Akt phosphorylation. Subsequently, TBMS1 inhibited DNA synthesis and induced G2/M phase arrest by targeting the PI3K/Akt/p21 and the cyclin‑dependent kinase 1/cyclin B1 signaling cascades. In addition, TBMS1 triggered apoptosis via the PI3K/Akt‑mediated Bcl‑2 signaling pathway. These results demonstrated that TBMS1 prevented the progression of gliomas via the PI3K/Akt‑dependent pathway, which provided a theoretical basis for in vivo studies to use TBMS1 as potential therapy for the prevention of cancer.

View Figures

View References

1	Diamandis P and Aldape K: World Health Organization 2016 Classification of Central Nervous System Tumors. Neurol Clin. 36:439–447. 2018. View Article : Google Scholar : PubMed/NCBI
2	Shi J, Dong B, Cao J, Mao Y, Guan W, Peng Y and Wang S: Long non-coding RNA in glioma: Signaling pathways. Oncotarget. 8:27582–27592. 2017. View Article : Google Scholar : PubMed/NCBI
3	Cloughesy TF, Cavenee WK and Mischel PS: Glioblastoma: From molecular pathology to targeted treatment. Annu Rev Pathol. 9:1–25. 2014. View Article : Google Scholar : PubMed/NCBI
4	Olar A and Aldape KD: Using the molecular classification of glioblastoma to inform personalized treatment. J Pathol. 232:165–177. 2014. View Article : Google Scholar : PubMed/NCBI
5	Yu L, Ma R, Wang Y and Nishino H: Potent anti-tumor activity and low toxicity of tubeimoside 1 isolated from Bolbostemma paniculatum. Planta Med. 60:204–208. 1994. View Article : Google Scholar : PubMed/NCBI
6	Zhang XH, Sun NX, Guo RX, Xing JL and Liu XN: Efficacy research of tubeimoside against the experimental herpes simplex keratitis. Rec Adv Ophthalmol. 22:373–376. 2002.
7	He D, Huang B, Fu S, Li Y, Ran X, Liu Y, Chen G, Liu J, Liu D and Tubeimoside I: Tubeimoside I protects dopaminergic neurons against inflammation-mediated damage in lipopolysaccharide (LPS)-evoked model of Parkinson's disease in rats. Int J Mol Sci. 19:E22422018. View Article : Google Scholar : PubMed/NCBI
8	Islam MS, Wang C, Zheng J, Paudyal N, Zhu Y and Sun H: The potential role of tubeimosides in cancer prevention and treatment. Eur J Med Chem. 162:109–121. 2019. View Article : Google Scholar : PubMed/NCBI
9	Jia G, Wang Q, Wang R, Deng D, Xue L, Shao N, Zhang Y, Xia X, Zhi F and Yang Y: Tubeimoside-1 induces glioma apoptosis through regulation of Bax/Bcl-2 and the ROS/Cytochrome C/Caspase-3 pathway. Onco Targets Ther. 8:303–311. 2015.PubMed/NCBI
10	Wu T, Cui H, Xu Y, Du Q, Zhao E, Cao J, Nie L, Fu G and Ren A: The effect of tubeimoside-1 on the proliferation, metastasis and apoptosis of oral squamous cell carcinoma in vitro. OncoTargets Ther. 11:3989–4000. 2018. View Article : Google Scholar
11	Jiang SL, Guan YD, Chen XS, Ge P, Wang XL, Lao YZ, Xiao SS, Zhang Y, Yang JM, Xu XJ, et al: Tubeimoside-1, a triterpenoid saponin, induces cytoprotective autophagy in human breast cancer cells in vitro via Akt-mediated pathway. Acta Pharmacol Sin. 40:919–928. 2019. View Article : Google Scholar : PubMed/NCBI
12	Baryawno N, Sveinbjörnsson B, Eksborg S, Chen CS, Kogner P and Johnsen JI: Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth. Cancer Res. 70:266–276. 2010. View Article : Google Scholar : PubMed/NCBI
13	Shi H, Bi H, Sun X, Dong H, Jiang Y, Mu H, Li W, Liu G, Gao R and Su J: Tubeimoside-1 inhibits the proliferation and metastasis by promoting miR-126-5p expression in non-small cell lung cancer cells. Oncol Lett. 16:3126–3134. 2018.PubMed/NCBI
14	Srivastav AK, Dubey D, Chopra D, Singh J, Negi S, Mujtaba SF, Dwivedi A and Ray RS: Oxidative stress-mediated photoactivation of carbazole inhibits human skin cell physiology. J Cell Biochem. 121:1273–1282. 2020. View Article : Google Scholar : PubMed/NCBI
15	Grier JT and Batchelor T: Low-grade gliomas in adults. Oncologist. 11:681–693. 2006. View Article : Google Scholar : PubMed/NCBI
16	Bush NA, Chang SM and Berger MS: Current and future strategies for treatment of glioma. Neurosurg Rev. 40:1–14. 2017. View Article : Google Scholar : PubMed/NCBI
17	Wang W, Gao W, Zhang L, Zhang D, Zhao Z and Bao Y: Deoxypodophyllotoxin inhibits cell viability and invasion by blocking the PI3K/Akt signaling pathway in human glioblastoma cells. Oncol Rep. 41:2453–2463. 2019.PubMed/NCBI
18	Ebrahimi S, Hosseini M, Shahidsales S, Maftouh M, Ferns GA, Ghayour-Mobarhan M, Hassanian SM and Avan A: Targeting the Akt/PI3K Signaling Pathway as a Potential Therapeutic Strategy for the Treatment of Pancreatic Cancer. Curr Med Chem. 24:1321–1331. 2017. View Article : Google Scholar : PubMed/NCBI
19	Yang Q, Jiang W and Hou P: Emerging role of PI3K/AKT in tumor-related epigenetic regulation. Semin Cancer Biol pii. S1044-579X(18)30136-6. 2019. View Article : Google Scholar
20	Fleischer A, Ghadiri A, Dessauge F, Duhamel M, Rebollo MP, Alvarez-Franco F and Rebollo A: Modulating apoptosis as a target for effective therapy. Mol Immunol. 43:1065–1079. 2006. View Article : Google Scholar : PubMed/NCBI
21	Li X, Wu C, Chen N, Gu H, Yen A, Cao L, Wang E and Wang L: PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget. 7:33440–33450. 2016. View Article : Google Scholar : PubMed/NCBI
22	Manning BD and Toker A: AKT/PKB signaling: Navigating the network. Cell. 169:381–405. 2017. View Article : Google Scholar : PubMed/NCBI
23	Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, et al: An integrated genomic analysis of human glioblastoma multiforme. Science. 321:1807–1812. 2008. View Article : Google Scholar : PubMed/NCBI
24	Wiman KG and Zhivotovsky B: Understanding cell cycle and cell death regulation provides novel weapons against human diseases. J Intern Med. 281:483–495. 2017. View Article : Google Scholar : PubMed/NCBI
25	Williams GH and Stoeber K: The cell cycle and cancer. J Pathol. 226:352–364. 2012. View Article : Google Scholar : PubMed/NCBI
26	Arellano M and Moreno S: Regulation of CDK/cyclin complexes during the cell cycle. Int J Biochem Cell Biol. 29:559–573. 1997. View Article : Google Scholar : PubMed/NCBI
27	Yang R, Yi L, Dong Z, Ouyang Q, Zhou J, Pang Y, Wu Y, Xu L and Cui H: Tigecycline inhibits glioma growth by regulating miRNA-199b-5p-HES1-AKT pathway. Mol Cancer Ther. 15:421–429. 2016. View Article : Google Scholar : PubMed/NCBI
28	Robertson JD and Orrenius S: Molecular mechanisms of apoptosis induced by cytotoxic chemicals. Crit Rev Toxicol. 30:609–627. 2000. View Article : Google Scholar : PubMed/NCBI
29	Creagh EM: Caspase crosstalk: Integration of apoptotic and innate immune signalling pathways. Trends Immunol. 35:631–640. 2014. View Article : Google Scholar : PubMed/NCBI
30	Kvansakul M and Hinds MG: Structural biology of the Bcl-2 family and its mimicry by viral proteins. Cell Death Dis. 4:e9092013. View Article : Google Scholar : PubMed/NCBI
31	Soriano ME and Scorrano L: The interplay between BCL-2 family proteins and mitochondrial morphology in the regulation of apoptosis. Adv Exp Med Biol. 687:97–114. 2010. View Article : Google Scholar : PubMed/NCBI
32	Forbes-Hernández TY, Giampieri F, Gasparrini M, Mazzoni L, Quiles JL, Alvarez-Suarez JM and Battino M: The effects of bioactive compounds from plant foods on mitochondrial function: A focus on apoptotic mechanisms. Food Chem Toxicol. 68:154–182. 2014. View Article : Google Scholar : PubMed/NCBI
33	Palmer CS, Osellame LD, Stojanovski D and Ryan MT: The regulation of mitochondrial morphology: Intricate mechanisms and dynamic machinery. Cell Signal. 23:1534–1545. 2011. View Article : Google Scholar : PubMed/NCBI
34	Zhang Y, Xu X and He P: Tubeimoside-1 inhibits proliferation and induces apoptosis by increasing the Bax to Bcl-2 ratio and decreasing COX-2 expression in lung cancer A549 cells. Mol Med Rep. 4:25–29. 2011.PubMed/NCBI
35	Chen WJ, Yu C, Yang Z, He JL, Yin J, Liu HZ, Liu HT and Wang YX: Tubeimoside-1 induces G2/M phase arrest and apoptosis in SKOV-3 cells through increase of intracellular Ca²⁺ and caspase-dependent signaling pathways. Int J Oncol. 40:535–543. 2012.PubMed/NCBI
36	Chao Y, Wang Y, Liu X, Ma P, Shi Y, Gao J, Shi Q, Hu J, Yu R and Zhou X: Mst1 regulates glioma cell proliferation via the AKT/mTOR signaling pathway. J Neurooncol. 121:279–288. 2015. View Article : Google Scholar : PubMed/NCBI