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Shikonin suppresses diffuse large B-cell lymphoma progression by inducing ferritinophagy and ferroptosis via lncRNA
Can Chen1, Xiaofei Chen2, Xilian Huang1
1Department of Hematology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China.
Abstract:
Shikonin, a natural compound, exhibits antitumor effects in DLBCL, but its mechanism remains unclear. Shikonin's cytotoxicity in DLBCL cells was assessed by MTT assays. Ferroptosis and lipid peroxidation markers were analysed via flow cytometry and biochemical kits. Mechanisms were explored using gene knockdown/overexpression, dual-luciferase assays, RNA pull-down, proteomics, RIP, FISH, and ChIP. Key proteins and genes involved in ferritinophagy and ferroptosis were examined by Western blot, RT-qPCR, and immunofluorescence, with findings validated in a nude mouse xenograft model. Shikonin triggers ferritinophagy and ferroptosis by increasing iron accumulation and lipid peroxidation. LncRNA ADPGK-AS1 protects against ferroptosis by regulating MT2A via eIF4G1 interaction. Shikonin triggers ferritinophagy and ferroptosis by disrupting iron metabolism and redox balance. The eIF4G1-ADPGK-AS1/MT2A axis mitigates these effects, revealing shikonin's antitumor mechanism and therapeutic potential.
Insights
Shikonin induces antitumor effects in diffuse large B-cell lymphoma (DLBCL) by triggering ferritinophagy and ferroptosis. A specific lncRNA pathway involving ADPGK-AS1 and MT2A mitigates these effects, revealing shikonin
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Shikonin, a natural compound, shows promise for treating diffuse large B-cell lymphoma (DLBCL).
- The precise molecular mechanisms underlying shikonin's antitumor activity in DLBCL are not fully understood.
Purpose of the Study:
- To elucidate the mechanism of shikonin's antitumor effects in DLBCL.
- To investigate shikonin's role in inducing ferritinophagy and ferroptosis.
- To identify key molecular players and pathways involved in shikonin's action.
Main Methods:
- Cytotoxicity assessed via MTT assays.
- Ferroptosis and lipid peroxidation markers analyzed using flow cytometry and biochemical kits.
- Mechanisms explored through gene manipulation, luciferase assays, RNA pull-down, proteomics, RIP, FISH, and ChIP.
- Protein and gene expression validated by Western blot, RT-qPCR, and immunofluorescence.
- In vivo validation using a nude mouse xenograft model.
Main Results:
- Shikonin induces ferritinophagy and ferroptosis in DLBCL cells by increasing iron accumulation and lipid peroxidation.
- The long non-coding RNA (lncRNA) ADPGK-AS1 was identified to protect against ferroptosis by regulating MT2A through interaction with eIF4G1.
- Shikonin disrupts iron metabolism and redox balance, while the eIF4G1-ADPGK-AS1/MT2A axis counteracts these effects.
Conclusions:
- Shikonin exerts its antitumor effects in DLBCL by inducing ferritinophagy and ferroptosis.
- The eIF4G1-ADPGK-AS1/MT2A axis plays a crucial role in modulating ferroptosis and shikonin's efficacy.
- These findings highlight shikonin's therapeutic potential and provide insights into its anticancer mechanism.
