Weiguo Chen

Author(s): Ponthier, Julie L.; Schluepen, Christina; Chen, Weiguo; Lersch, Robert A.; Gee, Sherry L.; Hou, Victor C.; Lo, Annie J.; Short, Sarah A.; Chasis, Joel A.; Winkelmann, John C.; Conboy, John G.

Nrf2 (NF-E2-related factor 2) is a master regulator of cellular oxidative levels against environmental stresses. Nrf2 induces the expression of metabolic detoxification and antioxidant enzymes to eliminate reactive oxygen species (ROS). The gastrointestinal tract is a key source of ROS. Intestinal barrier is critical to maintain the healthy steady state of the human gastrointestinal tract. Nrf2 has been shown to play important roles in maintaining the integrity of intestinal mucosal barrier. Here, we made a systematic review on the roles of Nrf2 in maintaining intestinal barrier, including the following: (1) NRF2 reduced intestinal mucosal injury by suppressing oxidative stress; (2) NRF2 decreased intestinal inflammation by inhibiting the inflammatory pathway; (3) NRF2 affected intestinal tight junction proteins and apoptosis of cells to regulate intestinal permeability; (4) NRF2 affected T cell differentiation and functions; (5) the crossregulation between the KEAP1-NRF2 pathway and autophagy controlled intestinal oxidative stress.

Background Triple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC. Methods In this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification. Results We found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8 + T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression. Conclusions Hence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC.