Growth inhibition and apoptosis by an active component of OK-432, a streptococcal agent, via Toll-like receptor 4 in human head and neck cancer cell lines
Growth inhibition and apoptosis by an active component of OK-432, a streptococcal agent, via Toll-like receptor 4 in human head and neck cancer cell lines
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DOI：
10.1016/j.oraloncology.2012.02.005
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发表时间：
2012-08-01
期刊：
影响因子：
4.8
通讯作者：
Hamakawa, Hiroyuki
中科院分区：
文献类型：
--
作者：
Tano, Tomoyuki;Okamoto, Masato;Hamakawa, Hiroyuki
Toll样受体4（TLR 4）作为细菌源性免疫抑制剂如OK-432（一种链球菌免疫抑制剂）的受体在癌症治疗中起重要作用。此外，最近的报道表明，TLR，包括TLR 4，也在癌细胞以及免疫活性细胞中表达。癌症治疗中的一个问题是，免疫佐剂可能通过TLR激活癌细胞中的存活信号，例如核因子（NF）-κ B或促分裂原活化蛋白激酶（MAPK）。在本研究中，我们研究了人头颈癌细胞系对TLR 4配体、OK-432的活性成分OK-PSA和脂多糖（LPS）的反应性，LPS或OK-PSA刺激导致表达TLR 4和MD-2的这些细胞系中NF-κ B的激活，MD-2是TLR 4信号传导的重要辅助受体。有趣的是，OK-PSA诱导细胞生长抑制，而LPS增强癌细胞的增殖。OK-PSA诱导的NF-κ B B活化较LPS慢。与LPS相比，OK-PSA对p38 MAPK的磷酸化程度较低。OK-432的活性成分通过激活caspase 1、3和8而非p53依赖性地诱导头颈癌细胞凋亡，提示OK-432的活性成分可能通过增强宿主免疫力以及通过TLR 4信号直接诱导头颈癌细胞生长抑制和凋亡而发挥抗癌作用。(c)2012爱思唯尔有限公司保留所有权利。
Toll-like receptor 4 (TLR4) plays a significant role in cancer therapy as receptors of bacteria-derived immunotherapeutic agents such as OK-432, a streptococcal immunotherapeutic agent. In addition, recent reports demonstrated that TLRs, including TLR4, are also expressed in cancer cells as well as in immunocompetent cells. It is a problem in cancer therapy that the immunoadjuvant may activate survival signals such as nuclear factor (NF)-kappa B or mitogen-activated protein kinases (MAPKs) in cancer cells via TLRs. In the current study, we investigated responsiveness of human head and neck cancer cell lines against TLR4 ligands, OK-PSA, an active component of OK-432, and a lipopolysaccharide (LPS).Stimulation with LPS or OK-PSA resulted in the activation of NF-kappa B in these cell lines expressing TLR4 and MD-2 that is a significant coreceptor for TLR4 signaling. Interestingly, OK-PSA induced cell-growth inhibition, while LPS enhanced the proliferation of the cancer cells. OK-PSA induced NF-kappa B activation more slowly than that induced by LPS. In addition, phosphorylation of p38 MAPK by OK-PSA was only slight compared with that by LPS. OK-PSA also induced apoptosis of the cancer cells mediated by the activation of caspase 1, 3 and 8 in a p53-independent manner.These findings strongly suggest that active components of OK-432 may elicit anti-cancer effects via enhancing host immunity as well as via directly inducing the growth inhibition and apoptosis of head and neck cancer cells through TLR4 signal. (c) 2012 Elsevier Ltd. All rights reserved.