Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNF alpha

Simple SummaryTumour necrosis factor alpha (TNF alpha) is a cytokine that plays an important role in apoptosis, cell survival, as well as in inflammation and immunity. Although named for its antitumor properties, TNF alpha has tumour-promoting properties. TNF alpha is often present in large quantities in tumours, and cancer cells frequently acquire resistance to this cytokine. Identifying the means to sensitise the cancer cells to TNF alpha would have therapeutical benefits. We, therefore, sought to determine whether inhibition of RNA polymerase III (Pol III), which synthesises several essential components of the protein biosynthetic machinery, would affect the response of cancer cells to TNF alpha. Here we show that Pol III inhibition augments the cytotoxic and cytostatic effects of TNF alpha. Our data suggest that targeting Pol III may be a potential therapeutic intervention to treat colorectal cancer. Tumour necrosis factor alpha (TNF alpha) is a multifunctional cytokine that plays a pivotal role in apoptosis, cell survival, as well as in inflammation and immunity. Although named for its antitumor properties, TNF alpha also has tumour-promoting properties. TNF alpha is often present in large quantities in tumours, and cancer cells frequently acquire resistance to this cytokine. Consequently, TNF alpha may increase the proliferation and metastatic potential of cancer cells. Furthermore, the TNF alpha-driven increase in metastasis is a result of the ability of this cytokine to induce the epithelial-to-mesenchymal transition (EMT). Overcoming the resistance of cancer cells to TNF alpha may have a potential therapeutic benefit. NF-kappa B is a crucial transcription factor mediating inflammatory signals and has a wide-ranging role in tumour progression. NF-kappa B is strongly activated in response to TNF alpha and contributes to cell survival and proliferation. The pro-inflammatory and pro-survival function of NF-kappa B can be disrupted by blocking macromolecule synthesis (transcription, translation). Consistently, inhibition of transcription or translation strongly sensitises cells to TNF alpha-induced cell death. RNA polymerase III (Pol III) synthesises several essential components of the protein biosynthetic machinery, such as tRNA, 5S rRNA, and 7SL RNA. No studies, however, directly explored the possibility that specific inhibition of Pol III activity sensitises cancer cells to TNF alpha. Here we show that in colorectal cancer cells, Pol III inhibition augments the cytotoxic and cytostatic effects of TNF alpha. Pol III inhibition enhances TNF alpha-induced apoptosis and also blocks TNF alpha-induced EMT. Concomitantly, we observe alterations in the levels of proteins related to proliferation, migration, and EMT. Finally, our data show that Pol III inhibition is associated with lower NF-kappa B activation upon TNF alpha treatment, thus potentially suggesting the mechanism of Pol III inhibition-driven sensitisation of cancer cells to this cytokine.