Inducing ubiquitination and degradation of TrxR1 protein by LW-216 promotes apoptosis in non-small cell lung cancer via triggering ROS production

• DOI: 10.1016/j.neo.2024.101004
• Publication Date: 2024-05-11T01:47:01Z
• Authors: Runde Wang; Liuyi Zhong; Tiepeng Wang; Tifan Sun; Jinming Yang; XinYe Liu; Yifan Wu; Qinglong Guo; Yuan Gao; Kai Zhao
• Keywords: Auranofin

Thioredoxin reductases are frequently overexpressed in various solid tumors as a protective mechanism against heightened oxidative stress. Inhibitors of this system, such Auranofin, effective eradicating cancer cells. However, the clinical significance thioredoxin reductase 1 (TrxR1) lung cancer, well potential for its antagonist treatment option, necessitated further experimental validation. In study, we observed significant upregulation TrxR1 specifically non-small cell (NSCLC), rather than small cancer. Moreover, expression exhibited associations with survival rate, tumor volume, and histological classification. We developed novel inhibitor named LW-216 assessed antitumor efficacy NSCLC. Our results revealed that is effectively bound intracellular at sites R371 G442, facilitating ubiquitination suppressing expression, while not affecting TrxR2 expression. Treatment LW-216-induced DNA damage apoptosis NSCLC cells through generation reactive oxygen species (ROS). Importantly, supplementation N-acetylcysteine (NAC) or ectopic reversed apoptosis. Furthermore, displayed potent growth inhibition cell-implanted mice, reducing xenografts. Remarkably, superior activity compared to Auranofin vivo. Collectively, our research provides compelling evidence supporting targeting by promising therapeutic strategy