p38MAPK activation mediates tumor necrosis factor-α‑induced apoptosis in glioma cells

Zhang,Bicheng; Wu,Tingting; Wang,Zhigang; Zhang,Yafei; Wang,Jun; Yang,Bo; Zhao,Yong; Rao,Zhiguo; Gao,Jianfei

doi:10.3892/mmr.2014.3002

p38MAPK activation mediates tumor necrosis factor-α‑induced apoptosis in glioma cells

Authors:
- Bicheng Zhang
- Tingting Wu
- Zhigang Wang
- Yafei Zhang
- Jun Wang
- Bo Yang
- Yong Zhao
- Zhiguo Rao
- Jianfei Gao
View Affiliations

Affiliations: Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army, Wuhan, Hubei 430070, P.R. China, Department of Oncology, General Hospital, Jinan Command of People's Liberation Army, Jinan, Shandong 250031, P.R. China
Published online on: November 26, 2014 https://doi.org/10.3892/mmr.2014.3002
Pages: 3101-3107

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

Gliomas are a type of heterogeneous primary central nervous system tumor, which arise from the glial cells; these types of tumor generally respond poorly to surgery, radiation and conventional chemotherapy. Tumor necrosis factor‑α (TNF‑α) has been suggested to produce an antitumor effect by binding to specific receptors on the tumor cell membrane to induce apoptosis. TNF‑α is known to activate a number of signaling pathways, including extracellular signal‑regulated protein kinase, c‑Jun N‑terminal kinase (JNK), p38 mitogen‑activated protein kinase (p38MAPK), nuclear factor‑κB and caspase cascades, depending on the cell type. However, the involvement of p38MAPK signaling in TNF‑α‑induced apoptosis in glioma cells remains unclear. In the current study, the role of p38MAPK in TNF‑α‑induced apoptosis in rat glioma C6 cells was investigated. TNF‑α was observed to induce cell apoptosis and the phosphorylation of p38MAPK in C6 cells. In addition, the inhibition of p38MAPK markedly reduced TNF‑α‑induced apoptosis, while JNK inhibition did not affect apoptosis. Furthermore, p38MAPK transfection altered the cell cycle of glioma cells and increased the rate of apoptosis. It also led to an increase in the level of soluble TNF‑α in the culture supernatant and membrane TNF receptor I levels in tumor cells. In conclusion, the results of the current study demonstrated that the activation of p38MAPK mediates TNF‑α‑induced apoptosis in glioma C6 cells, suggesting p38MAPK as a potential target for glioma therapy.

View Figures

View References

1	Sawyer TK, Shakespeare WC, Wang Y, et al: Protein phosphorylation and signal transduction modulation: chemistry perspectives for small-molecule drug discovery. Med Chem. 1:293–319. 2005. View Article : Google Scholar
2	Brown MD and Sacks DB: Protein scaffolds in MAP kinase signalling. Cell Signal. 21:462–469. 2009. View Article : Google Scholar :
3	Rana A, Rana B, Mishra R, et al: Mixed lineage kinase-c-Jun N-terminal kinase axis: a potential therapeutic target in cancer. Genes Cancer. 4:334–341. 2013. View Article : Google Scholar : PubMed/NCBI
4	Fischer S, Koeberle SC and Laufer SA: p38α mitogen-activated protein kinase inhibitors, a patent review (2005–2011). Expert Opin Ther Pat. 21:1843–1866. 2011. View Article : Google Scholar : PubMed/NCBI
5	Cohen P: The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends Cell Biol. 7:353–361. 1997. View Article : Google Scholar
6	Borders AS, de Almeida L, Van Eldik LJ and Watterson DM: The p38alpha mitogen-activated protein kinase as a central nervous system drug discovery target. BMC Neurosci. 9(Suppl 2): S122008. View Article : Google Scholar
7	Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 270:1326–1331. 1995. View Article : Google Scholar : PubMed/NCBI
8	Zechner D, Craig R, Hanford DS, McDonough PM, Sabbadini RA and Glembotski CC: MKK6 activates myocardial cell NF-kappaB and inhibits apoptosis in a p38 mitogen-activated protein kinase-dependent manner. J Biol Chem. 273:8232–8239. 1998. View Article : Google Scholar : PubMed/NCBI
9	Remacle-Bonnet MM, Garrouste FL, Heller S, André F, Marvaldi JL and Pommier GJ: Insulin-like growth factor-I protects colon cancer cells from death factor-induced apoptosis by potentiating tumor necrosis factor alpha-induced mitogen-activated protein kinase and nuclear factor kappaB signaling pathways. Cancer Res. 60:2007–2017. 2000.PubMed/NCBI
10	Zidi I, Mestiri S, Bartegi A and Amor NB: TNF-alpha and its inhibitors in cancer. Med Oncol. 27:185–198. 2010. View Article : Google Scholar
11	Szlosarek PW and Balkwill FR: Tumour necrosis factor alpha: a potential target for the therapy of solid tumours. Lancet Oncol. 4:565–573. 2003. View Article : Google Scholar : PubMed/NCBI
12	Gray-Schopfer VC, Karasarides M, Hayward R and Marais R: Tumor necrosis factor-alpha blocks apoptosis in melanoma cells when BRAF signaling isinhibited. Cancer Res. 67:122–129. 2007. View Article : Google Scholar : PubMed/NCBI
13	Sun SY, Yue P, Hong WK and Lotan R: Augmentation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by the synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) through up-regulation of TRAIL receptors in human lung cancer cells. Cancer Res. 60:7149–7155. 2000.
14	Barbin G, Roisin M and Zalc B: Tumor necrosis factor α activates the phosphorylation of ERK, SAPK/JNK, and P38 kinase in primary cultures of neurons. Neurochem Res. 26:107–112. 2001. View Article : Google Scholar : PubMed/NCBI
15	Valladares A, Alvarez AM, Ventura JJ, Roncero C, Benito M and Porras A: p38 mitogen-activated protein kinase mediates tumor necrosis factor-alpha-induced apoptosis in rat fetal brown adipocytes. Endocrinology. 141:4383–4395. 2000.PubMed/NCBI
16	Lüschen S, Scherer G, Ussat S, Ungefroren H and Adam-Klages S: Inhibition of p38 mitogen-activated protein kinase reduces TNF-induced activation of NF-kappaB, elicits caspase activity, and enhances cytotoxicity. Exp Cell Res. 293:196–206. 2004. View Article : Google Scholar : PubMed/NCBI
17	Ricote M, García-Tuñón I, Fraile B, Fernández C, Aller P, Paniagua R and Royuela M: P38 MAPK protects against TNF-alpha-provoked apoptosis in LNCaP prostatic cancer cells. Apoptosis. 11:1969–1975. 2006. View Article : Google Scholar : PubMed/NCBI
18	Yang X, Yao J, Luo Y, Han Y, Wang Z and Du L: P38 MAP kinase mediates apoptosis after genipin treatment in non-small-cell lung cancer H1299 cells via a mitochondrial apoptotic cascade. J Pharmacol Sci. 121:272–281. 2013. View Article : Google Scholar : PubMed/NCBI
19	Bradford MM: A rapid and sensitive for the quantitation of microgram quantitites of protein utilizing the principle of protein-dye binding. Analytical Biochemistry. 72:248–254. 1976. View Article : Google Scholar
20	Allegra A, Alonci A, Campo S, Penna G, Petrungaro A, Gerace D and Musolino C: Circulating microRNAs: new biomarkers in diagnosis, prognosis and treatment of cancer (review). Int J Oncol. 41:1897–1912. 2012.PubMed/NCBI
21	Yin D, Kondo S, Barnett GH, Morimura T and Takeuchi J: Tumor necrosis factor-alpha induces p53-dependent apoptosis in rat glioma cells. Neurosurgery. 37:758–763. 1995. View Article : Google Scholar : PubMed/NCBI
22	Han J, Lee JD, Bibbs L and Ulevitch RJ: A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. 265:808–811. 1994. View Article : Google Scholar : PubMed/NCBI
23	Ashwell JD: The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat Rev Immunol. 6:532–540. 2006. View Article : Google Scholar : PubMed/NCBI
24	Cuadrado A and Nebreda AR: Mechanisms and functions of p38 MAPK signalling. Biochem J. 429:403–17. 2010. View Article : Google Scholar : PubMed/NCBI
25	Ishii A, Furusho M and Bansal R: Sustained activation of ERK1/2 MAPK in oligodendrocytes and schwann cells enhances myelin growth and stimulates oligodendrocyte progenitor expansion. J Neurosci. 33:175–186. 2013. View Article : Google Scholar : PubMed/NCBI
26	Park MT, Choi JA, Kim MJ, et al: Suppression of extracellular signal-related kinase and activation of p38 MAPK are two critical events leading to caspase-8- and mitochondria-mediated cell death in phytosphingosine-treated human cancer cells. J Biol Chem. 278:50624–50634. 2003. View Article : Google Scholar : PubMed/NCBI
27	Mandal C, Dutta A, Mallick A, Chandra S, Misra L, Sangwan RS and Mandal C: Withaferin A induces apoptosis by activating p38 mitogen-activated kinase signaling cascade in leukemic cells of lymphoid and myeloid origin through mitochondrial death cascade. Apoptosis. 13:1450–1464. 2008. View Article : Google Scholar : PubMed/NCBI
28	Ozaki I, Tani E, Ikemoto H, Kitagawa H and Fujikawa H: Activation of stress-activated protein kinase/c-Jun NH2-terminal kinase and p38 kinase in calphostin C-induced apoptosis requires caspase-3-like proteases but is dispensable for cell death. J Biol Chem. 274:5310–5317. 1999. View Article : Google Scholar : PubMed/NCBI
29	Kanagasabai R, Karthikeyan K, Vedam K, Qien W, Zhu Q and Ilangovan G: Hsp27 protects adenocarcinoma cells from UV-induced apoptosis by Akt and p21-dependent pathways of survival. Mol Cancer Res. 8:1399–1412. 2010. View Article : Google Scholar : PubMed/NCBI
30	Park JG, Yuk Y, Rhim H, Yi SY and Yoo YS: Role of p38 MAPK in the regulation of apoptosis signaling induced by TNF-alpha in differentiated PC12 cells. J Biochem Mol Biol. 35:267–272. 2002. View Article : Google Scholar : PubMed/NCBI
31	Sun CL and Chao CC: Potential attenuation of p38 signaling by DDB2 as a factor in acquired TNF resistance. Int J Cancer. 115:383–387. 2005. View Article : Google Scholar : PubMed/NCBI
32	Lin CY, Chang SL, Fong YC, Hsu CJ and Tang CH: Apoptosis signal-regulating kinase 1 is involved in brain-derived neurotrophic factor (BDNF)-enhanced cell motility and matrix metalloproteinase 1 expression in human chondrosarcoma cells. Int J Mol Sci. 14:15459–15478. 2013. View Article : Google Scholar : PubMed/NCBI
33	Won M, Park KA, Byun HS, et al: Novel anti-apoptotic mechanism of A20 through targeting ASK1 to suppress TNF-induced JNK activation. Cell Death Differ. 17:1830–1841. 2010. View Article : Google Scholar : PubMed/NCBI
34	Morita Y, Naka T, Kawazoe Y, et al: Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosis factor alpha-induced cell death in fibroblasts. Proc Natl Acad Sci USA. 97:5405–5410. 2000. View Article : Google Scholar : PubMed/NCBI
35	Noguchi K, Yamana H, Kitanaka C, Mochizuki T, Kokubu A and Kuchino Y: Differential role of the JNK and p38 MAPK pathway in c-Myc- and s-Myc-mediated apoptosis. Biochem Biophys Res Commun. 267:221–227. 2000. View Article : Google Scholar : PubMed/NCBI
36	Cho SD, Ahn NS, Jung JW, et al: Critical role of the c-JunNH2-terminal kinase and p38 mitogen-activated protein kinase pathways on sodium butyrate-induced apoptosis in DU145 human prostate cancer cells. Eur J Cancer Prev. 15:57–63. 2006. View Article : Google Scholar
37	Van Laethem A, Van Kelst S, Lippens S, et al: Activation of p38 MAPK is required for Bax translocation to mitochondria, cytochrome c release and apoptosis induced by UVB irradiation in human keratinocytes. FASEB J. 18:1946–1948. 2004.PubMed/NCBI
38	Keller D, Zeng X, Li X, et al: The p38MAPK inhibitor SB203580 alleviates ultraviolet-induced phosphorylation at serine 389 but not serine 15 and activation of p53. Biochem Biophys Res Commun. 261:464–471. 1999. View Article : Google Scholar : PubMed/NCBI
39	Bhat NR, Zhang PS, Lee JC and Hogan EL: Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J Neurosci. 18:1633–1641. 1998.PubMed/NCBI
40	Donnahoo KK, Shames BD, Harken AH and Meldrum DR: Review article: the role of tumor necrosis factor in renal ischemia-reperfusion injury. J Urol. 162:196–203. 1999. View Article : Google Scholar : PubMed/NCBI
41	Ichijo H, Nishida E, Irie K, et al: Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 275:90–94. 1997. View Article : Google Scholar : PubMed/NCBI