Division of Life Science, Department of Applied Biochemistry, College of Health and Biomedical Science, Konkuk University, Chungju, Korea.
Mol Carcinog. 2014 Feb;53 Suppl 1:E23-35. doi: 10.1002/mc.21990. Epub 2012 Dec 19.
Interleukin (IL)-32 is a recently discovered cytokine that appears to play an important role in human colon cancer growth. We investigated that IL-32γ in combination with TNF-α remarkably inhibited cell growth of human colon cancer cells (HCT116 and SW620) and tumor growth in xenograft-bearing nude mice. The transient enforced overexpression of IL-32γ potentiated the inhibitory effect of TNF-α on DNA synthesis, cell number and protein content, and enhanced apoptosis in colon cancer cells. We also found that knockdown of IL-32γ by siRNA showed the abolishment of cell growth inhibitory effect of TNF-α. The IL-32γ-overexpressing colon cancer cells further increased TNF-α-mediated expression of p38 MAPK as well as that of Bax, cleaved caspase-3 and -9, but decreased that of antiapoptotic proteins such as Bcl-2, cellular inhibitor of apoptosis protein (IAP) and X chromosome IAP. In xenograft model, the lipopolysaccharide (LPS)-injected (1.25 mg/kg) mice inoculated with IL-32γ-transfected HCT116 colon cancer cells were more decrease tumor volume and weight than inoculated with vector. Tumor tissues isolated from LPS-injected mice inoculated with IL-32γ-overexpressing colon cancer cells potentiated the expression levels of pro-apoptotic proteins such as cleaved caspase-3, 9 and Bax, but decreased that of Bcl-2. Furthermore, the mice increased IL-10 production, but decreased IL-6 levels in serum. In conclusion, our results suggest that IL-32γ may potentiate TNF-α-induced cell growth inhibition through activation of p38 MAPK pathways.
白细胞介素 (IL)-32 是一种新发现的细胞因子，似乎在人类结肠癌的生长中发挥着重要作用。我们研究了 IL-32γ 与 TNF-α 的联合作用，发现其能显著抑制人结肠癌细胞（HCT116 和 SW620）的生长，并抑制荷瘤裸鼠的肿瘤生长。瞬时过表达 IL-32γ 增强了 TNF-α 对 DNA 合成、细胞数量和蛋白含量的抑制作用，并增强了结肠癌细胞的凋亡。我们还发现，siRNA 敲低 IL-32γ 可消除 TNF-α 的细胞生长抑制作用。过表达 IL-32γ 的结肠癌细胞进一步增加了 TNF-α 介导的 p38 MAPK 表达，以及 Bax、cleaved caspase-3 和 -9 的表达，但降低了 Bcl-2、细胞凋亡抑制蛋白（IAP）和 X 染色体 IAP 等抗凋亡蛋白的表达。在异种移植模型中，与转染空载体的 HCT116 结肠癌细胞相比，用 LPS（1.25mg/kg）处理的接种了 IL-32γ 转染的 HCT116 结肠癌细胞的小鼠肿瘤体积和重量明显减小。从 LPS 处理的接种了过表达 IL-32γ 的结肠癌细胞的小鼠中分离出的肿瘤组织，其 cleaved caspase-3、9 和 Bax 的表达水平升高，而 Bcl-2 的表达水平降低。此外，与接种空载体的小鼠相比，接种过表达 IL-32γ 的结肠癌细胞的小鼠血清中 IL-10 水平升高，IL-6 水平降低。综上所述，我们的研究结果表明，IL-32γ 可能通过激活 p38 MAPK 途径增强 TNF-α 诱导的细胞生长抑制作用。
