|Title:||The anti-apoptotic role of interleukin-6 in human cervical cancer is mediated by up-regulation of Mcl-1 through a PI 3-K/Akt pathway||Authors:||LING-HUNG WEI
|Issue Date:||2001||Journal Volume:||5799||Journal Issue:||5809||Start page/Pages:||5799-5809||Source:||Oncogene||Abstract:||
Interleukin-6 (IL-6), a multifunctional cytokine, has recently been implicated in human cervical cancer, though the mechanism remains elusive. This study demonstrates that the anti-apoptotic protein Mcl-1 and IL-6 was concomitantly expressed in human cervical cancer tissues and cell lines, but not in normal cervix tissues. Upon IL-6 treatment, Mcl-1, but not other Bcl-2 family members, was rapidly up-regulated peaking at 4-8 h in human cervical cancer C33A cells. Supporting this observation, using anti-IL-6 or anti-IL-6 receptor anti-body to interrupt the IL-6 autocrine loop in SiHa cells significantly reduced cellular level of Mcl-1. This study hypothesizes that the expression of Mcl-1 in cervical cancer cells is regulated by IL-6. The matter of which signaling pathways transduced by IL-6 is responsible for the Mcl-1 up-regulation is further investigated herein. Blocking the STAT3 or MAPK pathway with dominant-negative mutant STAT3F or the MEK inhibitor PD98059 failed to inhibit IL-6-mediated Mcl-1 expression. Meanwhile, the IL-6-induced Mcl-1 up-regulation was effectively abolished by treatment with PI 3-K inhibitors, LY294002. Additionally, overexpression of dominant-negative (dn) Akt in C33A cells could inhibit the IL-6-induced increase of Mcl-1. Finally, overexpression of IL-6 in C33A cells caused a markable resistance to apoptosis induced by doxorubicin or cisplatin. Transient transfection of IL-6-overexpressed cells with a mcl-1 antisense vector, leading to the attenuation of their apoptosis-resistant activity. In conclusion, the data herein suggest that IL-6 regulated the mcl-1 expression via a PI 3-K/Akt-dependent pathway that may facilitate the oncogenesis of human cervical cancer by modulating the apoptosis threshold.
|URI:||https://scholars.lib.ntu.edu.tw/handle/123456789/452814||DOI:||10.1038/sj.onc.1204733||SDG/Keyword:||2 (2 amino 3 methoxyphenyl)chromone; 2 morpholino 8 phenylchromone; cisplatin; doxorubicin; interleukin 6; mitogen activated protein kinase; phosphatidylinositol 3 kinase; protein mcl 1; STAT3 protein; apoptosis; article; autocrine effect; cancer cell culture; carcinogenesis; controlled study; female; genetic transfection; human; human cell; priority journal; protein expression; protein family; signal transduction; uterine cervix cancer; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Doxorubicin; Female; Green Fluorescent Proteins; Hela Cells; Humans; Interleukin-6; Luminescent Proteins; Neoplasm Proteins; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Transfection; Tumor Cells, Cultured; Up-Regulation; Uterine Cervical Neoplasms
|Appears in Collections:||醫學系|
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