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Published on: March 15, 2024
Arteannuin B Induces Ferroptosis in Colorectal Cancer Cells via GDF15/HMGCS1/GPX4 Axis
Xiaozheng Ou1,2, Jinghong Xu2, Yuting Jin2
1Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou, China.
Purpose:
Drug resistance in colorectal cancer (CRC) necessitates novel therapeutic strategies. This study investigated whether arteannuin B, a sesquiterpene lactone from Artemisia annua, induces ferroptosis in CRC cells and elucidated the underlying molecular mechanism.
Methods:
Anti-CRC effects were assessed via MTT assays and xenograft models. Proteomics identified differentially expressed proteins. Arteannuin B-induced ferroptosis was confirmed by measuring reactive oxygen species (ROS), lipid peroxidation, Fe²⁺ content, glutathione peroxidase 4 (GPX4) expression, and mitochondrial morphology. Mevalonate pathway regulation was evaluated by western blotting, dual-luciferase assay, and quantification of squalene, coenzyme Q10 (CoQ10), and cholesterol. The role of growth differentiation factor 15 (GDF15) was validated using shRNA knockdown and overexpression DLD-1 cells in vitro and in vivo.
Results:
Arteannuin B showed significant anti-colorectal cancer activity both in vitro and in vivo. The proteomic analysis demonstrated that arteannuin B affected the mevalonate pathway and ferroptosis in DLD-1 cells, and strongly upregulated the expression of GDF15. Arteannuin B increased ROS, lipid peroxidation, malondialdehyde, and iron while decreasing GPX4 expression and causing mitochondrial shrinkage. Arteannuin B inhibited mevalonate pathway enzymes, particularly 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), reducing squalene, CoQ10, and cholesterol. The knockdown of GDF15 weakened the inhibitory effect of arteannuin B on the mevalonate pathway and GPX4, and reduced the sensitivity of CRC cells to arteannuin B both in vitro and in vivo.
Conclusion:
Arteannuin B triggers ferroptosis-like cell death in CRC cells and suppresses xenograft growth, in association with inhibition of the mevalonate pathway. GDF15 contributes to arteannuin B-mediated suppression of HMGCS1 and GPX4 and to ferroptosis sensitivity.
Insights
Arteannuin B, derived from Artemisia annua, effectively combats colorectal cancer (CRC) by inducing ferroptosis, a form of cell death. This sesquiterpene lactone targets the mevalonate pathway and enhances CRC cell sensitivity to this cell death mechanism.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Colorectal cancer (CRC) drug resistance necessitates novel therapeutic approaches.
- Arteannuin B, a sesquiterpene lactone from Artemisia annua, is explored for its anti-cancer potential.
Purpose of the Study:
- To investigate if arteannuin B induces ferroptosis in colorectal cancer cells.
- To elucidate the molecular mechanisms underlying arteannuin B's effects on CRC.
Main Methods:
- Cell viability assays (MTT) and xenograft models assessed anti-CRC effects.
- Proteomics, ROS, lipid peroxidation, Fe²⁺, GPX4, and mitochondrial morphology evaluated ferroptosis.
- Mevalonate pathway analysis involved western blotting and metabolite quantification.
- GDF15's role was studied using knockdown and overexpression cell lines.
Main Results:
- Arteannuin B demonstrated significant anti-CRC activity in vitro and in vivo.
- Proteomics revealed arteannuin B impacts the mevalonate pathway and ferroptosis, upregulating GDF15.
- Arteannuin B increased oxidative stress markers and iron, decreased GPX4, and altered mitochondrial morphology.
- Inhibition of mevalonate pathway enzymes (HMGCS1) and downstream metabolites (squalene, CoQ10, cholesterol) was observed.
- GDF15 knockdown attenuated arteannuin B's effects on the mevalonate pathway, GPX4, and CRC cell sensitivity.
Conclusions:
- Arteannuin B induces ferroptosis-like cell death in CRC cells and inhibits tumor growth by targeting the mevalonate pathway.
- GDF15 plays a crucial role in mediating arteannuin B's effects on HMGCS1, GPX4, and ferroptosis sensitivity in CRC.
