LW-213, a derivative of wogonin, triggers reticulophagy-mediated cell death in NSCLC via lysosomal damage combined with NPC1 inhibition.

BACKGROUND

Maintaining intracellular equilibrium is essential for the viability of tumor cells, which tend to be particularly vulnerable to environmental stressors. Consequently, targeting the disruption of this homeostasis offers a promising approach for oncological treatments. LW-213, a novel derivative of wogonin, effectively induces apoptosis in cancer cells by initiating endoplasmic reticulum (ER) stress, although the precise molecular pathways involved remain intricate and multifaceted.

PURPOSE

This research aimed to explore how LW-213 prompts apoptosis in non-small cell lung cancer (NSCLC) cells and to clarify the detailed mechanisms that govern this process.

METHODS

Various NSCLC cell lines were utilized to delineate the apoptotic effects induced by LW-213. Advanced methodologies, including RNA sequencing (RNA-seq), Western blotting (WB), immunofluorescence (IF), immunoprecipitation (IP), flow cytometry (Fc), real-time quantitative polymerase chain reaction (RT-qPCR), and electron microscopy, were employed to investigate the underlying molecular interactions. The efficacy and mechanistic action of LW-213 were also assessed in a xenograft model using nude mice.

RESULTS

We demonstrated that LW-213, a small molecule cationic amphiphilic drug (CAD), inhibited Niemann-Pick C1 (NPC1) function and induced lysosomal membrane damage, thereby activating the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway. This activation promoted cholesterol transport from the ER to the lysosome, perpetuating a cholesterol-deficient state in the ER, including massive exocytosis of Ca and activation of FAM134B-mediated reticulophagy. Ultimately, excessive reticulophagy induced lethal ER stress.

CONCLUSIONS

In summary, our study elucidates an organelle domino reaction initiated by lysosome damage and a series of self-rescue mechanisms that eventually lead to irreversible lethal effects, revealing a potential drug intervention strategy.