Di Benedetto Carolina, Khan Taimoor, Serrano-Saenz Santiago, Rodriguez-Lemus Anthony, Klomsiri Chananat, Beutel Tim-Mathis, Thach Alysia, Walczak Henning, Betancur Paola
Department of Radiation Oncology, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA.
CECAD Cluster of Excellence, University of Cologne, 50931 Cologne, Germany.
Cancers (Basel). 2023 Feb 3;15(3):967. doi: 10.3390/cancers15030967.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine produced and secreted by immune cells in response to an infection, often in response to interferon (IFN) stimulation. In cancer, it has also been shown that IFN stimulates the production of TRAIL, and it has been proposed that this TRAIL can induce apoptosis in an autocrine or paracrine manner in different cancer cells. Yet, the mechanism mediating TRAIL upregulation and the implications of TRAIL as an apoptotic molecule in cancer cells are still poorly understood. We show here that in certain cancer cells, TRAIL is upregulated by enhancer clusters, potent genomic regulatory regions containing densely packed enhancers that have combinatorial and additive activity and that are usually found to be associated with cancer-promoting genes. Moreover, we found that TRAIL upregulation by IFNα is mediated by these enhancer clusters in breast and lung cancer cells. Surprisingly, IFNα stimulation leads to the intracellular accumulation of TRAIL protein in these cancer cells. Consequently, this TRAIL is not capable of inducing apoptosis. Our study provides novel insights into the mechanism behind the interferon-mediated upregulation of TRAIL and its protein accumulation in cancer cells. Further investigation is required to understand the role of intracellular TRAIL or depict the mechanisms mediating its apoptosis impairment in cancer cells.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是免疫细胞在受到感染时，通常是在干扰素（IFN）刺激下产生并分泌的一种细胞因子。在癌症中，也已表明IFN会刺激TRAIL的产生，并且有人提出这种TRAIL可以以自分泌或旁分泌的方式在不同癌细胞中诱导凋亡。然而，介导TRAIL上调的机制以及TRAIL作为癌细胞中凋亡分子的意义仍知之甚少。我们在此表明，在某些癌细胞中，TRAIL由增强子簇上调，增强子簇是强大的基因组调控区域，含有紧密排列的增强子，具有组合和累加活性，通常发现与促癌基因相关。此外，我们发现IFNα在乳腺癌和肺癌细胞中通过这些增强子簇介导TRAIL上调。令人惊讶的是，IFNα刺激导致这些癌细胞中TRAIL蛋白在细胞内积累。因此，这种TRAIL不能诱导凋亡。我们的研究为干扰素介导的TRAIL上调及其在癌细胞中蛋白积累背后的机制提供了新的见解。需要进一步研究以了解细胞内TRAIL的作用或描述介导其在癌细胞中凋亡受损的机制。
