Luteolin reduces migration of human glioblastoma cell lines via inhibition of the p‑IGF‑1R/PI3K/AKT/mTOR signaling pathway

Wang,Qiang; Wang,Handong; Jia,Yue; Ding,Hui; Zhang,Li; Pan,Hao

doi:10.3892/ol.2017.6643

Luteolin reduces migration of human glioblastoma cell lines via inhibition of the p‑IGF‑1R/PI3K/AKT/mTOR signaling pathway

Authors:
- Qiang Wang
- Handong Wang
- Yue Jia
- Hui Ding
- Li Zhang
- Hao Pan
View Affiliations

Affiliations: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, P.R. China, Department of Neurosurgery, Jinling Hospital, School of Medicine, Southern Medical University, Nanjing, Jiangsu 210002, P.R. China
Published online on: July 21, 2017 https://doi.org/10.3892/ol.2017.6643
Pages: 3545-3551
Copyright: © Wang 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

Luteolin (3',4',5,7-tetrahydroxyflavone) is a common dietary flavonoid, which has been demonstrated to exert anticancer effects in multiple cancer models. However, the detailed mechanisms underlying the inhibitory effect of luteolin on glioblastoma cell metastasis remain poorly understood. The present study assessed the effects of luteolin in the U251MG and U87MG human glioblastoma cell lines. Luteolin treatment significantly inhibited glioblastoma cell migration, and this effect was associated with downregulated matrix metalloproteinase (MMP)‑2, MMP‑9 and upregulated tissue inhibitor of metalloproteinase (TIMP)‑1 and TIMP‑2. In addition, luteolin also inhibited the epithelial-mesenchymal transition-associated phenotype. Furthermore, the phosphorylated insulin‑like growth factor‑1 receptor/phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin (p‑IGF‑1R/PI3K/AKT/mTOR) signaling pathway was demonstrated to participate in these processes. The results of the present study demonstrated that the flavonoid luteolin reduced the migration of glioblastoma cells by altering p‑IGF‑1R/PI3K/AKT/mTOR activation, and may have potential applications for chemoprevention in a clinical setting.

View Figures

View References

1	Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, Stroup NE, Kruchko C and Barnholtz-Sloan JS: CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncol. 15:(Suppl 2). ii1–ii56. 2013. View Article : Google Scholar : PubMed/NCBI
2	Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI
3	Lin Y, Shi R, Wang X and Shen HM: Luteolin, a flavonoid with potentials for cancer prevention and therapy. Curr Cancer Drug Targets. 8:634–646. 2008. View Article : Google Scholar : PubMed/NCBI
4	Moon YJ, Wang X and Morris ME: Dietary flavonoids: Effects on xenobiotic and carcinogen metabolism. Toxicol In Vitro. 20:187–210. 2006. View Article : Google Scholar : PubMed/NCBI
5	Chian S, Thapa R, Chi Z, Wang XJ and Tang X: Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo. Biochem Biophys Res Commun. 447:602–608. 2014. View Article : Google Scholar : PubMed/NCBI
6	Chang J, Hsu Y, Kuo P, Kuo Y, Chiang L and Lin C: Increase of Bax/Bcl-XL ratio and arrest of cell cycle by luteolin in immortalized human hepatoma cell line. Life Sci. 76:1883–1893. 2005. View Article : Google Scholar : PubMed/NCBI
7	Lee HJ, Wang CJ, Kuo HC, Chou FP, Jean LF and Tseng TH: Induction apoptosis of luteolin in human hepatoma HepG2 cells involving mitochondria translocation of Bax/Bak and activation of JNK. Toxicol Appl Pharmacol. 203:124–131. 2005. View Article : Google Scholar : PubMed/NCBI
8	Lim DY, Jeong Y, Tyner AL and Park JH: Induction of cell cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin. Am J Physiol Gastrointest Liver Physiol. 292:G66–G75. 2007. View Article : Google Scholar : PubMed/NCBI
9	Tang X, Wang H, Fan L, Wu X, Xin A, Ren H and Wang XJ: Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs. Free Radic Biol Med. 50:1599–1609. 2011. View Article : Google Scholar : PubMed/NCBI
10	Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA and Abbott NJ: Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic Biol Med. 36:592–604. 2004. View Article : Google Scholar : PubMed/NCBI
11	Jang S, Kelley KW and Johnson RW: Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci USA. 105:7534–7539. 2008. View Article : Google Scholar : PubMed/NCBI
12	Hendriks JJ, Alblas J, van der Pol SM, van Tol EA, Dijkstra CD and de Vries HE: Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis. J Exp Med. 200:1667–1672. 2004. View Article : Google Scholar : PubMed/NCBI
13	Etienne-Manneville S: In vitro assay of primary astrocyte migration as a tool to study Rho GTPase function in cell polarization. Methods Enzymol. 406:565–578. 2006. View Article : Google Scholar : PubMed/NCBI
14	Subramani R, Lopez-Valdez R, Arumugam A, Nandy S, Boopalan T and Lakshmanaswamy R: Targeting insulin-like growth factor 1 receptor inhibits pancreatic cancer growth and metastasis. PLoS One. 9:e970162014. View Article : Google Scholar : PubMed/NCBI
15	Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M, Mikulits W, Brabletz T, Strand D, Obrist P, et al: The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene. 26:6979–6988. 2007. View Article : Google Scholar : PubMed/NCBI
16	Hazan RB, Qiao R, Keren R, Badano I and Suyama K: Cadherin switch in tumor progression. Ann N Y Acad Sci. 1014:155–163. 2004. View Article : Google Scholar : PubMed/NCBI
17	Baserga R, Peruzzi F and Reiss K: The IGF-1 receptor in cancer biology. Int J Cancer. 107:873–877. 2003. View Article : Google Scholar : PubMed/NCBI
18	King H, Aleksic T, Haluska P and Macaulay VM: Can we unlock the potential of IGF-1R inhibition in cancer therapy? Cancer Treat Rev. 40:1096–1105. 2014. View Article : Google Scholar : PubMed/NCBI
19	Yin S, Girnita A, Strömberg T, Khan Z, Andersson S, Zheng H, Ericsson C, Axelson M, Nistér M, Larsson O, et al: Targeting the insulin-like growth factor-1 receptor by picropodophyllin as a treatment option for glioblastoma. Neuro Oncol. 12:19–27. 2010. View Article : Google Scholar : PubMed/NCBI
20	Kim YS, Lee HA, Lim JY and Kim Y, Jung CH, Yoo SH and Kim Y: β-Carotene inhibits neuroblastoma cell invasion and metastasis in vitro and in vivo by decreasing level of hypoxia-inducible factor-1α. J Nutr Biochem. 25:655–664. 2014. View Article : Google Scholar : PubMed/NCBI
21	Hiraoka N, Allen E, Apel IJ, Gyetko MR and Weiss SJ: Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell. 95:365–377. 1998. View Article : Google Scholar : PubMed/NCBI
22	Lu KW, Chen JC, Lai TY, Yang JS, Weng SW, Ma YS, Lu PJ, Weng JR, Chueh FS, Wood WG and Chung JG: Gypenosides inhibits migration and invasion of human oral cancer SAS cells through the inhibition of matrix metalloproteinase-2 −9 and urokinase-plasminogen by ERK1/2 and NF-kappa B signaling pathways. Hum Exp Toxicol. 30:406–415. 2011. View Article : Google Scholar : PubMed/NCBI
23	Brew K, Dinakarpandian D and Nagase H: Tissue inhibitors of metalloproteinases, evolution, structure and function. Biochim Biophys Acta. 1477:267–283. 2000. View Article : Google Scholar : PubMed/NCBI
24	Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 7:131–142. 2006. View Article : Google Scholar : PubMed/NCBI
25	Raftopoulou M and Hall A: Cell migration: Rho GTPases lead the way. Dev Biol. 265:23–32. 2004. View Article : Google Scholar : PubMed/NCBI
26	Clemmons DR: Modifying IGF1 activity: An approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov. 6:821–833. 2007. View Article : Google Scholar : PubMed/NCBI
27	Wojtalla A, Salm F, Christiansen DG, Cremona T, Cwiek P, Shalaby T, Gross N, Grotzer MA and Arcaro A: Novel agents targeting the IGF-1R/PI3K pathway impair cell proliferation and survival in subsets of medulloblastoma and neuroblastoma. PLoS One. 7:e471092012. View Article : Google Scholar : PubMed/NCBI
28	Wang JY, Del Valle L, Gordon J, Rubini M, Romano G, Croul S, Peruzzi F, Khalili K and Reiss K: Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas. Oncogene. 20:3857–3868. 2001. View Article : Google Scholar : PubMed/NCBI
29	Yin S, Girnita A, Stromberg T, Khan Z, Andersson S, Zheng H, Ericsson C, Axelson M, Nistér M, Larsson O, et al: Targeting the insulin-like growth factor-1 receptor by picropodophyllin as a treatment option for glioblastoma. Neuro Oncol. 12:19–27. 2010. View Article : Google Scholar : PubMed/NCBI
30	Cheng CK, Fan QW and Weiss WA: PI3K signaling in glioma-animal models and therapeutic challenges. Brain Pathol. 19:112–120. 2009. View Article : Google Scholar : PubMed/NCBI