Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612.
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612;
Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11482-11487. doi: 10.1073/pnas.1705536114. Epub 2017 Oct 9.
Cancer cells are adept at evading cell death, but the underlying mechanisms are poorly understood. IL-12 plays a critical role in the early inflammatory response to infection and in the generation of T-helper type 1 cells, favoring cell-mediated immunity. IL-12 is composed of two different subunits, p40 and p35. This study underlines the importance of IL-12 p40 monomer (p40) in helping cancer cells to escape cell death. We found that different mouse and human cancer cells produced greater levels of p40 than p40 homodimer (p40), IL-12, or IL-23. Similarly, the serum level of p40 was much greater in patients with prostate cancer than in healthy control subjects. Selective neutralization of p40, but not p40, by mAb stimulated death in different cancer cells in vitro and in vivo in a tumor model. Interestingly, p40 was involved in the arrest of IL-12 receptor (IL-12R) IL-12Rβ1, but not IL-12Rβ2, in the membrane, and that p40 neutralization induced the internalization of IL-12Rβ1 via caveolin and caused cancer cell death via the IL-12-IFN-γ pathway. These studies identify a role of p40 monomer in helping cancer cells to escape cell death via suppression of IL-12Rβ1 internalization.
癌细胞善于逃避细胞死亡，但潜在机制仍不清楚。IL-12 在感染的早期炎症反应和辅助性 T 细胞 1 型细胞的产生中发挥关键作用，有利于细胞介导的免疫。IL-12 由两个不同的亚基组成，p40 和 p35。本研究强调了 IL-12 p40 单体（p40）在帮助癌细胞逃避细胞死亡方面的重要性。我们发现不同的鼠和人癌细胞产生的 p40 水平高于 p40 同源二聚体（p40）、IL-12 或 IL-23。同样，前列腺癌患者血清中的 p40 水平明显高于健康对照组。在体外和肿瘤模型中，选择性中和 p40（而不是 p40）的 mAb 刺激不同癌细胞死亡。有趣的是，p40 参与了 IL-12 受体（IL-12R）IL-12Rβ1 的阻滞，但不是 IL-12Rβ2，在膜中，并且 p40 中和诱导了通过小窝蛋白导致的 IL-12Rβ1 的内化，并通过 IL-12-IFN-γ 途径导致癌细胞死亡。这些研究确定了 p40 单体在通过抑制 IL-12Rβ1 内化来帮助癌细胞逃避细胞死亡方面的作用。
