No abstract

Breast cancer (BC) is one of the most common malignant tumors found in females. Previous studies have demonstrated that curcumin, which is a type of polyphenol compound extracted from Curcuma longa underground rhizome, is able to inhibit the survival of cancer cells. However, the functional role and mechanism of curcumin in BC are still unclear. The Cell Counting Kit-8 assay was performed to examine the effects of curcumin on cell viability in the BC cell lines MDA-MB-453 and MCF-7. The levels of lipid reactive oxygen species (ROS), malondialdehyde (MDA) production, and intracellular Fe2+ were determined to assess the effects of curcumin on cell ferroptosis. Western blot analysis was also carried out to detect the protein levels. Finally, the antitumorigenic effect of curcumin on BC was identified in a xenograft tumor model. In the present study, the results indicated that curcumin could dose-dependently suppress the viability of both MDA-MB-453 and MCF-7 cells. Further studies revealed that curcumin facilitated solute carrier family 1 member 5 (SLC1A5)-mediated ferroptosis in both MDA-MB-453 and MCF-7 cells by enhancing lipid ROS levels, lipid peroxidation end-product MDA accumulation, and intracellular Fe2+ levels. In vivo experiments demonstrated that curcumin could significantly hamper tumor growth. Collectively, the results demonstrated that curcumin exhibited antitumorigenic activity in BC by promoting SLC1A5-mediated ferroptosis, which suggests its use as a potential therapeutic agent for the treatment of BC.

Nuclear factor κB (NF-κB) signaling is a central pathway that participates in a variety of key processes, including immunity, inflammation, cell growth and differentiation. The activity of NF-κB is strictly regulated by a cluster of proteins, and modifications of these proteins either promote or suppress signal transduction at various steps. Here we demonstrated that HSCARG suppresses TNFα-stimulated NF-κB signaling under physiological conditions. We elucidated the detailed mechanism through which HSCARG inhibits NF-κB activation. HSCARG interacts with NEMO and suppresses polyubiquitination of NEMO by interacting with the deubiquitinase USP7. HSACRG attenuates its inhibitory effect on NEMO ubiquitination in USP7 knockdown cells, and inhibition of NEMO polyubiquitination by USP7 is impaired in HSCARG−/− cells as well. Moreover, we demonstrated that USP7 is a negative regulator of TNFα-stimulated NF-κB activity. Altogether, our data indicate that HSCARG and USP7 function in concert in inhibiting polyubiquination of NEMO, thus inhibiting NF-κB activity.