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

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

  • Phytomedicine. 2024 Nov:134:155958. doi: 10.1016/j.phymed.2024.155958.
Hongzheng Wang 1,  Yuexin Jiang 1,  Mengyuan Zhu 1,  Hui Li 1,  Hongyu Chen 1,  Haidi Wang 1,  Shuai Zhang 2,  Qinglong Guo 3,  Hui Hui 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 2 The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 21009, PR China.
  • 3 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: anticancer_drug@163.com.
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: moyehh@163.com.
PMID: 39241385 DOI: 10.1016/j.phymed.2024.155958
Abstract

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 CA2+ 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.

Keywords

Cholesterol; Lysosome; NPC1; PITT; Reticulophagy; SREBP2.

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