Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways

被引:147
作者
Leu, CM
Wong, FH
Chang, CM
Huang, SF
Hu, CP [1 ]
机构
[1] Taipei Vet Gen Hosp, Dept Med Res & Educ, Taipei 112, Taiwan
[2] Natl Yang Ming Univ, Inst Microbiol & Immunol, Taipei 112, Taiwan
[3] Natl Yang Ming Univ, Inst Publ Hlth, Taipei 112, Taiwan
[4] Natl Hlth Res Inst, Dept Intramural Res Affairs, Taipei, Taiwan
[5] Natl Hlth Res Inst, Div Mol & Gen Med, Taipei, Taiwan
[6] Chang Gung Mem Hosp, Dept Pathol, Taipei 10591, Taiwan
关键词
IL-6; esophageal carcinoma; apoptosis; MAPK; STAT3;
D O I
10.1038/sj.onc.1207084
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The production of interleukin-6 (IL-6) has been discovered in a variety of human tumors. Here we report the expression of IL-6, IL-6 receptor alpha (IL- 6Ralpha), and gp130 in human esophageal carcinoma tissues. We further demonstrate that IL- 6 protects an esophageal carcinoma cell line CE48T/VGH from apoptosis induced by staurosporine. IL-6 stimulation induced a rapid phosphorylation of gp130 and STAT3, and a dominant-negative STAT3 completely abolished the antiapoptotic effect. IL-6 also activated ERK 1/2 in CE48T/VGH cells. Inhibition of the ERK activation by PD98059 and transfection of a dominant-negative ERK2 completely blocked the protection of IL- 6 against apoptosis. Thus, both STAT and MAP kinase pathways are responsible for the IL-6-delivered survival signal in human esophageal carcinoma cells. In contrast, PI3-K inhibitors only partially attenuated the effect of IL-6, suggesting that PI3-K does not play a major role in the antiapoptotic signal of IL- 6 in our system. To investigate whether IL- 6 could induce the production of antiapoptotic molecules, proteins of the Bcl-2 family were measured. While Bcl-2, Bcl- x(L),, and Bax were not affected, Mcl-1 was induced by IL-6 in human esophageal carcinoma cells. Our results suggest that IL- 6 may contribute to the progression of esophageal cancers in an autocrine or paracrine manner.
引用
收藏
页码:7809 / 7818
页数:10
相关论文
共 47 条
  • [1] The YXXQ motif in gp 130 is crucial for STAT3 phosphorylation at Ser727 through an H7-sensitive kinase pathway
    Abe, K
    Hirai, M
    Mizuno, K
    Higashi, N
    Sekimoto, T
    Miki, T
    Hirano, T
    Nakajima, K
    [J]. ONCOGENE, 2001, 20 (27) : 3464 - 3474
  • [2] BLOT WJ, 1994, SEMIN ONCOL, V21, P403
  • [3] Stat3 as an oncogene
    Bromberg, JF
    Wrzeszczynska, MH
    Devgan, G
    Zhao, YX
    Pestell, RG
    Albanese, C
    Darnell, JE
    [J]. CELL, 1999, 98 (03) : 295 - 303
  • [4] Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells
    Catlett-Falcone, R
    Landowski, TH
    Oshiro, MM
    Turkson, J
    Levitzki, A
    Savino, R
    Ciliberto, G
    Moscinski, L
    Fernández-Luna, JL
    Nuñez, G
    Dalton, WS
    Jove, R
    [J]. IMMUNITY, 1999, 10 (01) : 105 - 115
  • [5] Interleukin-6 inhibits transforming growth factor-β-induced apoptosis through the phosphatidylinositol 3-kinase/Akt and signal transducers and activators of transcription 3 pathways
    Chen, RH
    Chang, MC
    Su, YH
    Tsai, YT
    Kuo, ML
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (33) : 23013 - 23019
  • [6] CHEN T, 2001, CANCER RES, V60, P2132
  • [7] STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation
    Chung, JK
    Uchida, E
    Grammer, TC
    Blenis, J
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (11) : 6508 - 6516
  • [8] Enzinger PC, 1999, SEMIN ONCOL, V26, P12
  • [9] Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression
    Epling-Burnette, PK
    Liu, JH
    Catlett-Falcone, R
    Turkson, J
    Oshiro, M
    Kothapalli, R
    Li, YX
    Wang, JM
    Yang-Yen, HF
    Karras, J
    Jove, R
    Loughran, TP
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (03) : 351 - 361
  • [10] Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: Involvement of STAT3 in anti-apoptosis
    Fukada, T
    Hibi, M
    Yamanaka, Y
    TakahashiTezuka, M
    Fujitani, Y
    Yamaguchi, T
    Nakajima, K
    Hirano, T
    [J]. IMMUNITY, 1996, 5 (05) : 449 - 460