Enhanced radiosensitization and chemosensitization in NF-kappaB-suppressed human oral cancer cells via the inhibition of gamma-irradiation- and 5-FU-induced production of IL-6 and IL-8.
Enhanced radiosensitization and chemosensitization in NF-kappaB-suppressed human oral cancer cells via the inhibition of gamma-irradiation- and 5-FU-induced production of IL-6 and IL-8.
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发表时间：
2004
影响因子：
6.4
通讯作者：
T. Tamatani;M. Azuma;Y. Ashida;K. Motegi;R. Takashima;K. Harada;Shin-ichi Kawaguchi;Mitsunobu Sato
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作者：
T. Tamatani;M. Azuma;Y. Ashida;K. Motegi;R. Takashima;K. Harada;Shin-ichi Kawaguchi;Mitsunobu Sato
我们研究了人口腔癌细胞 (B88) 中 NF-κB 活性被组成性抑制的情况下，对 γ 辐射 (IR) 和 5-氟尿嘧啶 (5-FU) 的放射敏感性和化学敏感性增强的机制。已建立了 3 个超阻遏形式的 IkappaBalpha cDNA 转染细胞 (B88ml) 克隆和 1 个空载体转染细胞克隆 (B88neo)。我们发现B88mI克隆的裸鼠成瘤能力明显低于B88或B88neo。这种致瘤性受到抑制的能力归因于与 B88 或 B88neo 相比，B88mI 细胞克隆中白细胞介素 (IL)-1α、IL-6、IL-8、血管内皮生长因子 (VEGF) 和基质金属蛋白酶 (MMP)-9 的表达下调。流式细胞术分析和膜联蛋白V染色证明，IR和5-FU在B88mI细胞克隆中比在B88或B88neo中诱导更大程度的细胞凋亡。当用IR或5-FU处理荷瘤裸鼠时，与B88或B88neo相比，B88ml细胞克隆中的肿瘤生长抑制显着增强。 ELISA 分析表明，尽管在体外暴露于 IR 或用 5-FU 处理后，在 B88 和 B88neo 中观察到 IL-6 和 IL-8 的产生显着增加，但在 B88mI 细胞克隆中，放疗和化疗诱导的这些细胞因子的产生显着受到抑制。这些研究结果表明，放疗和化疗产生的血管生成因子和生长因子是人类口腔癌诱导放射抗性和化疗抗性的主要机制，并确立了抑制 NF-κB 作为改善常规放疗和化疗结果的合理方法。
We examined the mechanisms underlying the enhancement of radiosensitivity and chemosensitivity to gamma-irradiation (IR) and 5-Fluorouracil (5-FU) in human oral carcinoma cells (B88) in which NF-kappaB activity was constitutively suppressed. Three super-repressor form of IkappaBalpha cDNA-transfected cell (B88mI) clones and 1 empty vector-transfected cell clone (B88neo) have been established. We found that the tumor-forming ability in nude mice of B88mI clones was significantly lower than that of B88 or B88neo. This suppressed ability in tumorigenicity was attributed to the down-regulation of the expression of interleukin (IL)-1alpha, IL-6, IL-8, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 in B88mI cell clones as compared to that in B88 or B88neo. IR and 5-FU induced a much greater degree of apoptosis, as evidenced by flow cytometry analysis and annexin V staining, in B88mI cell clones than in B88 or B88neo. When tumor-bearing nude mice were treated with IR or 5-FU, the suppression of tumor growth was significantly augmented in B88mI cell clones as compared to that in B88 or B88neo. ELISA analysis indicated that although a remarkable increase in production of IL-6 and IL-8 was observed in B88 and B88neo after in vitro exposure to IR or treatment with 5-FU, radiotherapy and chemotherapy-induced production of these cytokines was significantly suppressed in B88mI cell clones. These findings suggest that production of angiogenic factors and growth factors in response to radiotherapy and chemotherapy is a principal mechanism of inducible radioresistance and chemoresistance in human oral cancers, and establish the inhibition of NF-kappaB as a rational approach to improve conventional radiotherapy and chemotherapy outcomes.