Research ArticlePharmacology

The transcription factor SP3 drives TNF-α expression in response to Smac mimetics

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Science Signaling  29 Jan 2019:
Vol. 12, Issue 566, eaat9563
DOI: 10.1126/scisignal.aat9563

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SP3 is key to Smac mimetic efficacy

Finding drugs that selectively target tumor cells and spare healthy tissue is a challenging goal. Smac mimetic compounds have emerged as promising cancer therapies by blocking anti-apoptotic machinery and inducing the production of the cytokine TNF-α. Beug et al. found not only that the transcription factor SP3 critically mediates the molecular and cellular effects of Smac mimetics but also that it is more abundantly expressed in tumors than in normal tissues from the same patients. These findings suggest that using SP3 as a biomarker may identify patients that will best respond to and tolerate these drugs.


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.

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