Honokiol induces autophagy and apoptosis of osteosarcoma through PI3K/Akt/mTOR signaling pathway

Li,Zhiquan; Dong,Hui; Li,Mo; Wu,Yaoping; Liu,Yanwu; Zhao,Yinan; Chen,Xiaochao; Ma,Minliang

doi:10.3892/mmr.2017.8123

Honokiol induces autophagy and apoptosis of osteosarcoma through PI3K/Akt/mTOR signaling pathway

Authors:
- Zhiquan Li
- Hui Dong
- Mo Li
- Yaoping Wu
- Yanwu Liu
- Yinan Zhao
- Xiaochao Chen
- Minliang Ma
View Affiliations

Affiliations: PLA Institute of Orthopedics and Traumatology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of Orthopedics, The 474th Hospital of PLA, Urumqi, Xinjiang 830013, P.R. China
Published online on: November 21, 2017 https://doi.org/10.3892/mmr.2017.8123
Pages: 2719-2723

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

Honokiol is the main active constituent of Magnolia officinalis. With effective and long‑term pharmacological functions of being antibacterial, anti‑oxidative, anti‑inflammatory, antitumor, anti‑spasmic, anti‑anxiety and anti‑viral, Honokiol is clinically used in the treatment of acute enteritis and chronic gastritis. The aim of the present study was to observe the possible anti‑effects of honokiol on autophagy and apoptosis of osteosarcoma, and to investigate the role of the PI3K/Akt/mTOR signaling pathway in its anticancer effects. MTT assay was used to evaluate cell proliferation and Annexin V‑fluorescein isothiocyanate/propidium iodide staining flow cytometry was used to analyze the apoptotic rate. The authors identified that honokiol could inhibit cell proliferation and induce the apoptotic rate of osteosarcoma cells. The expression level of Bcl‑2‑like protein 4, caspase‑3 and p53 protein expression were induced and cyclin D1 protein expression was suppressed in osteosarcoma cells by honokiol. Autophagy‑associated LC3II protein expression level was promoted, and PI3K, p‑Akt and p‑mTOR protein expression level was suppressed in osteosarcoma cells by honokiol. The present study demonstrated, to the best of the authors' knowledge, for the first time that honokiol induces autophagy and apoptosis of osteosarcoma cells through the PI3K/Akt/mTOR signaling pathway.

View Figures

View References

1	Nataraj V, Batra A, Rastogi S, Khan SA, Sharma MC, Vishnubhatla S and Bakhshi S: Developing a prognostic model for patients with localized osteosarcoma treated with uniform chemotherapy protocol without high dose methotrexate: A single-center experience of 237 patients. J Surg Oncol. 112:662–668. 2015. View Article : Google Scholar : PubMed/NCBI
2	Tai BC, Machin D, White I and Gebski V; EOI (The European Osteosarcoma Intergroup), : Competing risks analysis of patients with osteosarcoma: A comparison of four different approaches. Stat Med. 20:661–684. 2001. View Article : Google Scholar : PubMed/NCBI
3	London CA, Gardner HL, Mathie T, Stingle N, Portela R, Pennell ML, Clifford CA, Rosenberg MP, Vail DM, Williams LE, et al: Impact of toceranib/piroxicam/cyclophosphamide maintenance therapy on outcome of dogs with appendicular osteosarcoma following amputation and carboplatin chemotherapy: A multi-institutional study. PLoS One. 10:e01248892015. View Article : Google Scholar : PubMed/NCBI
4	Li L, Li Y, Zhao J, Fan S, Wang L and Li X: CX-5461 induces autophagy and inhibits tumor growth via mammalian target of rapamycin-related signaling pathways in osteosarcoma. Onco Targets Ther. 9:5985–5997. 2016. View Article : Google Scholar : PubMed/NCBI
5	Huang Q, Ou YS, Tao Y, Yin H and Tu PH: Apoptosis and autophagy induced by pyropheophorbide-a methyl ester-mediated photodynamic therapy in human osteosarcoma MG-63 cells. Apoptosis. 21:749–760. 2016. View Article : Google Scholar : PubMed/NCBI
6	Ma K, Zhang C, Huang MY, Li WY and Hu GQ: Cinobufagin induces autophagy-mediated cell death in human osteosarcoma U2OS cells through the ROS/JNK/p38 signaling pathway. Oncol Rep. 36:90–98. 2016. View Article : Google Scholar : PubMed/NCBI
7	Zhang B, Yu X and Xia H: The flavonoid luteolin enhances doxorubicin-induced autophagy in human osteosarcoma U2OS cells. Int J Clin Exp Med. 8:15190–15197. 2015.PubMed/NCBI
8	Zhou J, Wu S, Chen Y, Zhao J, Zhang K, Wang J and Chen S: microRNA-143 is associated with the survival of ALDH1+CD133+ osteosarcoma cells and the chemoresistance of osteosarcoma. Exp Biol Med (Maywood). 240:867–875. 2015. View Article : Google Scholar : PubMed/NCBI
9	Hu K, Dai HB and Qiu ZL: mTOR signaling in osteosarcoma: Oncogenesis and therapeutic aspects (Review). Oncol Rep. 36:1219–1225. 2016. View Article : Google Scholar : PubMed/NCBI
10	Zhang J, Yu XH, Yan YG, Wang C and Wang WJ: PI3K/Akt signaling in osteosarcoma. Clin Chim Acta. 444:182–192. 2015. View Article : Google Scholar : PubMed/NCBI
11	Wang Y, Sun Y, Wu Y and Zhang J: Cucurbitacin E inhibits osteosarcoma cells proliferation and invasion through attenuation of PI3K/AKT/mTOR signaling. Biosci Rep. pii:BSR201601652016.
12	Averett C, Bhardwaj A, Arora S, Srivastava SK, Khan MA, Ahmad A, Singh S, Carter JE, Khushman M and Singh AP: Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor-stromal cross-talk. Carcinogenesis. 37:1052–1061. 2016. View Article : Google Scholar : PubMed/NCBI
13	Herrmann D, Schreiber A, Ciotkowska A, Strittmatter F, Waidelich R, Stief CG, Gratzke C and Hennenberg M: Honokiol, a constituent of Magnolia species, inhibits adrenergic contraction of human prostate strips and induces stromal cell death. Prostate Int. 2:140–146. 2014. View Article : Google Scholar : PubMed/NCBI
14	Crane C, Panner A, Pieper RO, Arbiser J and Parsa AT: Honokiol-mediated inhibition of PI3K/mTOR pathway: A potential strategy to overcome immunoresistance in glioma, breast, and prostate carcinoma without impacting T cell function. J Immunother. 32:585–592. 2009. View Article : Google Scholar : PubMed/NCBI
15	Felgenhauer JL, Nieder ML, Krailo MD, Bernstein ML, Henry DW, Malkin D, Baruchel S, Chuba PJ, Sailer SL, Brown K, et al: A pilot study of low-dose anti-angiogenic chemotherapy in combination with standard multiagent chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma family of tumors: A Children's Oncology Group (COG) Phase II study NCT00061893. Pediatr Blood Cancer. 60:409–414. 2013. View Article : Google Scholar : PubMed/NCBI
16	Altaf S, Enders F, Jeavons E, Krailo M, Barkauskas DA, Meyers P and Arndt C: High-BMI at diagnosis is associated with inferior survival in patients with osteosarcoma: A report from the children's oncology group. Pediatr Blood Cancer. 60:2042–2046. 2013. View Article : Google Scholar : PubMed/NCBI
17	Yang C, Shogren KL, Goyal R, Bravo D, Yaszemski MJ and Maran A: RNA-dependent protein kinase is essential for 2-methoxyestradiol-induced autophagy in osteosarcoma cells. PLoS One. 8:e594062013. View Article : Google Scholar : PubMed/NCBI
18	Niu NK, Wang ZL, Pan ST, Ding HQ, Au GH, He ZX, Zhou ZW, Xiao G, Yang YX, Zhang X, et al: Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237) on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway. Drug Des Devel Ther. 9:1555–1584. 2015.PubMed/NCBI
19	Lv X, Liu F, Shang Y and Chen SZ: Honokiol exhibits enhanced antitumor effects with chloroquine by inducing cell death and inhibiting autophagy in human non-small cell lung cancer cells. Oncol Rep. 34:1289–1300. 2015. View Article : Google Scholar : PubMed/NCBI
20	Zhang H, Guo M, Chen JH, Wang Z, Du XF, Liu PX and Li WH: Osteopontin knockdown inhibits av, b3 integrin-induced cell migration and invasion and promotes apoptosis of breast cancer cells by inducing autophagy and inactivating the PI3K/Akt/mTOR pathway. Cell Physiol Biochem. 33:991–1002. 2014. View Article : Google Scholar : PubMed/NCBI
21	Li Y, Liu Y, Shi F, Cheng L and She J: Knockdown of Rap1b enhances apoptosis and autophagy in gastric cancer cells via the PI3K/Akt/mTOR pathway. Oncol Res. 24:287–293. 2016. View Article : Google Scholar : PubMed/NCBI
22	Bai H, Li H, Li W, Gui T, Yang J, Cao D and Shen K: The PI3K/AKT/mTOR pathway is a potential predictor of distinct invasive and migratory capacities in human ovarian cancer cell lines. Oncotarget. 6:25520–25532. 2015. View Article : Google Scholar : PubMed/NCBI
23	Roy R, Singh SK, Chauhan LK, Das M, Tripathi A and Dwivedi PD: Zinc oxide nanoparticles induce apoptosis by enhancement of autophagy via PI3K/Akt/mTOR inhibition. Toxicol Lett. 227:29–40. 2014. View Article : Google Scholar : PubMed/NCBI
24	Kumar D, Das B, Sen R, Kundu P, Manna A, Sarkar A, Chowdhury C, Chatterjee M and Das P: Andrographolide analogue induces apoptosis and autophagy mediated cell death in U937 cells by inhibition of PI3K/Akt/mTOR pathway. PLoS One. 10:e01396572015. View Article : Google Scholar : PubMed/NCBI
25	Xishan Z: Peer review report 1 on ‘P53 suppresses cell proliferation, metastasis, and angiogenesis of osteosarcoma through inhibition of the PI3K/AKT/mTOR pathway’. Int J Surg. 13 Suppl 1:S322015. View Article : Google Scholar
26	Liu Y, Bi T, Dai W, Wang G, Qian L, Shen G and Gao Q: Lupeol induces apoptosis and cell cycle arrest of human osteosarcoma cells through PI3K/AKT/mTOR pathway. Technol Cancer Res Treat. 15:NP16–NP24. 2016. View Article : Google Scholar : PubMed/NCBI
27	Lin CJ, Chen TL, Tseng YY, Wu GJ, Hsieh MH, Lin YW and Chen RM: Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway. Toxicol Appl Pharmacol. 304:59–69. 2016. View Article : Google Scholar : PubMed/NCBI