Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, 1050 Boyles Street, Frederick, MD, USA.
Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ, 08854-8020, USA.
Cell Death Dis. 2021 Nov 1;12(11):1038. doi: 10.1038/s41419-021-04318-y.
Cancer cells experience endoplasmic reticulum (ER) stress due to activated oncogenes and conditions of nutrient deprivation and hypoxia. The ensuing unfolded protein response (UPR) is executed by ATF6, IRE1 and PERK pathways. Adaptation to mild ER stress promotes tumor cell survival and aggressiveness. Unmitigated ER stress, however, will result in cell death and is a potential avenue for cancer therapies. Because of this yin-yang nature of ER stress, it is imperative that we fully understand the mechanisms and dynamics of the UPR and its contribution to the complexity of tumor biology. The PERK pathway inhibits global protein synthesis while allowing translation of specific mRNAs, such as the ATF4 transcription factor. Using thapsigargin and tunicamycin to induce acute ER stress, we identified the transcription factor C/EBPδ (CEBPD) as a mediator of PERK signaling to secretion of tumor promoting chemokines. In melanoma and breast cancer cell lines, PERK mediated early induction of C/EBPδ through ATF4-independent pathways that involved at least in part Janus kinases and the STAT3 transcription factor. Transcriptional profiling revealed that C/EBPδ contributed to 20% of thapsigargin response genes including chaperones, components of ER-associated degradation, and apoptosis inhibitors. In addition, C/EBPδ supported the expression of the chemokines CXCL8 (IL-8) and CCL20, which are known for their tumor promoting and immunosuppressive properties. With a paradigm of short-term exposure to thapsigargin, which was sufficient to trigger prolonged activation of the UPR in cancer cells, we found that conditioned media from such cells induced cytokine expression in myeloid cells. In addition, activation of the CXCL8 receptor CXCR1 during thapsigargin exposure supported subsequent sphere formation by cancer cells. Taken together, these investigations elucidated a novel mechanism of ER stress-induced transmissible signals in tumor cells that may be particularly relevant in the context of pharmacological interventions.
癌细胞由于激活的致癌基因以及营养剥夺和缺氧等条件而经历内质网（ER）应激。随之而来的未折叠蛋白反应（UPR）是由 ATF6、IRE1 和 PERK 途径执行的。轻度 ER 应激的适应性会促进肿瘤细胞的存活和侵袭性。然而，未缓解的 ER 应激会导致细胞死亡，这是癌症治疗的潜在途径。由于 ER 应激的这种阴阳性质，我们必须充分了解 UPR 的机制和动态及其对肿瘤生物学复杂性的贡献。PERK 途径抑制了全球蛋白质合成，同时允许特定 mRNA 的翻译，如 ATF4 转录因子。使用 thapsigargin 和 tunicamycin 诱导急性 ER 应激，我们确定转录因子 C/EBPδ（CEBPD）是 PERK 信号转导至肿瘤促进趋化因子分泌的介质。在黑色素瘤和乳腺癌细胞系中，PERK 通过 ATF4 非依赖性途径介导 C/EBPδ 的早期诱导，该途径至少部分涉及 Janus 激酶和 STAT3 转录因子。转录谱分析显示，C/EBPδ 有助于包括伴侣蛋白、内质网相关降解成分和凋亡抑制剂在内的 20%的 thapsigargin 反应基因。此外，C/EBPδ 支持趋化因子 CXCL8（IL-8）和 CCL20 的表达，这些趋化因子因其促进肿瘤和免疫抑制特性而闻名。在短暂暴露于 thapsigargin 的范例中，这足以触发癌症细胞中 UPR 的长期激活，我们发现来自这些细胞的条件培养基可诱导髓样细胞中的细胞因子表达。此外，在 thapsigargin 暴露期间激活 CXCL8 受体 CXCR1 支持随后癌细胞的球体形成。总之，这些研究阐明了 ER 应激诱导的肿瘤细胞中可传播信号的新机制，这在药理学干预的背景下可能特别相关。
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