Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.
Sci Signal. 2019 Jan 29;12(566):eaat9563. doi: 10.1126/scisignal.aat9563.
The controlled production and downstream signaling of the inflammatory cytokine tumor necrosis factor-α (TNF-α) are important for immunity and its anticancer effects. Although chronic stimulation with TNF-α is detrimental to the health of the host in several autoimmune and inflammatory disorders, TNF-α-contrary to what its name implies-leads to cancer formation by promoting cell proliferation and survival. Smac mimetic compounds (SMCs), small-molecule antagonists of inhibitor of apoptosis proteins (IAPs), switch the TNF-α signal from promoting survival to promoting death in cancer cells. Using a genome-wide siRNA screen to identify factors required for SMC-to-TNF-α-mediated cancer cell death, we identified the transcription factor SP3 as a critical molecule in both basal and SMC-induced production of TNF-α by engaging the nuclear factor κB (NF-κB) transcriptional pathway. Moreover, the promotion of TNF-α expression by SP3 activity confers differential sensitivity of cancer versus normal cells to SMC treatment. The key role of SP3 in TNF-α production and signaling will help us further understand TNF-α biology and provide insight into mechanisms relevant to cancer and inflammatory disease.
炎症细胞因子肿瘤坏死因子-α（TNF-α）的受控产生和下游信号转导对于免疫和抗癌作用非常重要。尽管慢性刺激 TNF-α会在几种自身免疫和炎症性疾病中对宿主健康造成损害，但 TNF-α——与它的名字所暗示的相反——通过促进细胞增殖和存活导致癌症形成。Smac 模拟物化合物（SMCs）是凋亡抑制蛋白（IAPs）的小分子拮抗剂，可将 TNF-α信号从促进存活转变为促进癌细胞死亡。我们使用全基因组 siRNA 筛选来鉴定 SMC 至 TNF-α介导的癌细胞死亡所需的因子，发现转录因子 SP3 通过参与核因子 κB（NF-κB）转录途径成为基础和 SMC 诱导的 TNF-α产生的关键分子。此外，SP3 活性促进 TNF-α表达赋予了癌症与正常细胞对 SMC 治疗的不同敏感性。SP3 在 TNF-α产生和信号转导中的关键作用将帮助我们进一步了解 TNF-α 生物学，并深入了解与癌症和炎症性疾病相关的机制。
