Mig-2 Attenuates Cisplatin-induced Apoptosis of Human Glioma Cells in Vitro Through AKT/JNK and AKT/p38 Signaling Pathways

Overview

Journal Acta Pharmacol Sin

Specialty Pharmacology

Date 2014 Aug 26

PMID 25152024

Citations 13

Authors

Yun-Wei Ou

Zi-Tong Zhao

Chuan-Yue Wu

Bai-Nan Xu

Yong-Mei Song

Qi-Min Zhan

Affiliations

Soon will be listed here.

Abstract

Aim: Mig-2 (also known as Kindlin-2 and FERMT2) is an important regulator of integrin activation and cell-extracellular matrix adhesion, and involved in carcinogenesis and tumor progression. The aim of this study was to investigate the role of mig-2 in cisplatin-induced apoptosis of human glioma cells in vitro.

Methods: The expression of mig-2 was modulated in human glioma H4, HS 683 and U-87 MG cells by transfection with a plasmid carrying mig-2 or mig-2 siRNA. Cisplatin-induced apoptosis was detected using Annexin V/PI staining and flow cytometry, as well as MTS analyses. The expression of apoptosis-related or signaling proteins was examined using Western blotting analysis. H4 cells were transfected with plasmids carrying mig-2 mutants to determine the functional domain of mig-2.

Results: In the 3 glioma cell lines tested, overexpression of mig-2 significantly attenuated cisplatin-induced apoptosis, whereas knock-down of mig-2 potentiated the apoptosis. The mechanisms of action of mig-2 were further addressed in H4 cells: overexpression of mig-2 markedly reduced cleaved caspase-9, caspase-8, caspase-3 and PARP, as well as p-JNK and p-p38, and increased p-AKT in cisplatin-treated H4 cells, whereas mig-2 siRNA reversely changed these apoptosis-related and signaling proteins. Furthermore, pretreatment with JNK inhibitor SP600125 and p38 inhibitor SB203580, or with AKT inhibitor LY294002 abolished the effects of mig-2 on cisplaxtin-induced apoptosis. In H4 cells, GFP-mig-2 F3 plasmid that contained only the F3 subdomain showed the same efficiency in attenuating cisplatin-induced apoptosis, as the mig-2 wild-type vector did, whereas GFP-mig-2 (1-541) plasmid that lacked the F3 subdomain was inactive.

Conclusion: Mig-2 significantly attenuates the antitumor action of cisplatin against human glioma cells in vitro through AKT/JNK and AKT/p38 signaling pathways. The F3 subdomain of mig-2 is necessary and sufficient for this effect.

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References

Liu W, Huang C, Lu I, Gean P . Inhibition of glioma growth by minocycline is mediated through endoplasmic reticulum stress-induced apoptosis and autophagic cell death. Neuro Oncol. 2013; 15(9):1127-41. PMC: 3748919. DOI: 10.1093/neuonc/not073. View

Wu C, Chen Z, Chen T, Liao J, Lin C, Chien M . Mitogen-activated protein kinases p38 and JNK mediate Actinobacillus pleuropneumoniae exotoxin ApxI-induced apoptosis in porcine alveolar macrophages. Vet Microbiol. 2011; 151(3-4):372-8. DOI: 10.1016/j.vetmic.2011.03.033. View

Kim R, Emi M, Tanabe K . Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol. 2005; 57(5):545-53. DOI: 10.1007/s00280-005-0111-7. View

Tian W, Zhang Z, Cohen D . MAPK signaling and the kidney. Am J Physiol Renal Physiol. 2000; 279(4):F593-604. DOI: 10.1152/ajprenal.2000.279.4.F593. View

Ou Y, Ma L, Dong L, Ma L, Zhao Z, Ma L . Migfilin protein promotes migration and invasion in human glioma through epidermal growth factor receptor-mediated phospholipase C-γ and STAT3 protein signaling pathways. J Biol Chem. 2012; 287(39):32394-405. PMC: 3463316. DOI: 10.1074/jbc.M112.393900. View

Hemmings B . Akt signaling: linking membrane events to life and death decisions. Science. 1997; 275(5300):628-30. DOI: 10.1126/science.275.5300.628. View

Gong X, An Z, Wang Y, Guan L, Fang W, Stromblad S . Kindlin-2 controls sensitivity of prostate cancer cells to cisplatin-induced cell death. Cancer Lett. 2010; 299(1):54-62. DOI: 10.1016/j.canlet.2010.08.003. View

Tu Y, Wu S, Shi X, Chen K, Wu C . Migfilin and Mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation. Cell. 2003; 113(1):37-47. DOI: 10.1016/s0092-8674(03)00163-6. View

Johannesen T, Langmark F, Lote K . Cause of death and long-term survival in patients with neuro-epithelial brain tumours: a population-based study. Eur J Cancer. 2003; 39(16):2355-63. DOI: 10.1016/s0959-8049(03)00603-8. View

10.

Ou Y, Ma L, Ma L, Huang Z, Zhou W, Zhao C . Overexpression of cyclin B1 antagonizes chemotherapeutic-induced apoptosis through PTEN/Akt pathway in human esophageal squamous cell carcinoma cells. Cancer Biol Ther. 2012; 14(1):45-55. PMC: 3566051. DOI: 10.4161/cbt.22627. View

11.

Jiang X, Wang X . Cytochrome C-mediated apoptosis. Annu Rev Biochem. 2004; 73:87-106. DOI: 10.1146/annurev.biochem.73.011303.073706. View

12.

Liu Y, Zhu Y, Ye S, Zhang R . Crystal structure of kindlin-2 PH domain reveals a conformational transition for its membrane anchoring and regulation of integrin activation. Protein Cell. 2012; 3(6):434-40. PMC: 4875484. DOI: 10.1007/s13238-012-2046-1. View

13.

Zhao T, Guan L, Yu Y, Pei X, Zhan J, Han L . Kindlin-2 promotes genome instability in breast cancer cells. Cancer Lett. 2012; 330(2):208-16. DOI: 10.1016/j.canlet.2012.11.043. View

14.

Ma Y, Qin J, Wu C, Plow E . Kindlin-2 (Mig-2): a co-activator of beta3 integrins. J Cell Biol. 2008; 181(3):439-46. PMC: 2364684. DOI: 10.1083/jcb.200710196. View

15.

Eskes R, Desagher S, Antonsson B, Martinou J . Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol. 2000; 20(3):929-35. PMC: 85210. DOI: 10.1128/MCB.20.3.929-935.2000. View

16.

Weaver R . Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades. Biochem J. 1998; 336 ( Pt 3):599-609. PMC: 1219910. DOI: 10.1042/bj3360599. View

17.

Shen Z, Ye Y, Kauttu T, Seppanen H, Vainionpaa S, Wang S . Novel focal adhesion protein kindlin-2 promotes the invasion of gastric cancer cells through phosphorylation of integrin β1 and β3. J Surg Oncol. 2013; 108(2):106-12. DOI: 10.1002/jso.23353. View

18.

Ghobrial I, Witzig T, Adjei A . Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin. 2005; 55(3):178-94. DOI: 10.3322/canjclin.55.3.178. View

19.

Hsiao P, Hsieh Y, Chow J, Yang S, Hsiao M, Hua K . Hispolon induces apoptosis through JNK1/2-mediated activation of a caspase-8, -9, and -3-dependent pathway in acute myeloid leukemia (AML) cells and inhibits AML xenograft tumor growth in vivo. J Agric Food Chem. 2013; 61(42):10063-73. DOI: 10.1021/jf402956m. View

20.

Almasan A, Ashkenazi A . Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev. 2003; 14(3-4):337-48. DOI: 10.1016/s1359-6101(03)00029-7. View