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β-Elemene induced ferroptosis via TFEB-mediated GPX4 degradation in EGFR wide-type non-small cell lung cancer
Li-Ping Zhao1, Hao-Jie Wang1, Die Hu1
1School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Introduction:
β-Elemene (β-ELE), derived from Curcuma wenyujin, has anticancer effect on non-small cell lung cancer (NSCLC). However, the potential target and detail mechanism were still not clear. TFEB is the master regulator of lysosome biogenesis. Ferroptosis, a promising strategy for cancer therapy could be triggered via suppression on glutathione peroxidase 4 (GPX4). Weather TFEB-mediated lysosome degradation contributes to GPX4 decline and how β-ELE modulates on this process are not clear.
Objectives:
To observe the action of β-ELE on TFEB, and the role of TFEB-mediated GPX4 degradation in β-ELE induced ferroptosis.
Methods:
Surface plasmon resonance (SPR) and molecular docking were applied to observe the binding affinity of β-ELE on TFEB. Activation of TFEB and lysosome were observed by immunofluorescence, western blot, flow cytometry and qPCR. Ferroptosis induced by β-ELE was observed via lipid ROS, a labile iron pool (LIP) assay and western blot. A549TFEB KO cells were established via CRISPR/Cas9. The regulation of TFEB on GPX4 and ferroptosis was observed in β-ELE treated A549WT and A549TFEB KO cells, which was further studied in orthotopic NOD/SCID mouse model.
Results:
β-ELE can bind to TFEB, notably activate TFEB, lysosome and transcriptional increase on downstream gene GLA, MCOLN1, SLC26A11 involved in lysosome activity in EGFR wild-type NSCLC cells. β-ELE increased GPX4 ubiquitination and lysosomal localization, with the increase on lysosome degradation of GPX4. Furthermore, β-ELE induced ferroptosis, which could be promoted by TFEB overexpression or compromised by TFEB knockout. Genetic knockout or inactivation of TFEB compromised β-ELE induced lysosome degradation of GPX4, which was further demonstrated in orthotopic NSCLC NOD/SCID mice model.
Conclusion:
This study firstly demonstrated that TFEB promoted GPX4 lysosome degradation contributes to β-ELE induced ferroptosis in EGFR wild-type NSCLC, which gives a clue that TFEB mediated GPX4 degradation would be a novel strategy for ferroptosis induction and NSCLC therapy.
Insights
Beta-elemene (β-ELE) activates TFEB, promoting lysosomal degradation of GPX4 and inducing ferroptosis in non-small cell lung cancer (NSCLC). This TFEB-mediated pathway offers a new therapeutic strategy for NSCLC.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Mechanisms
Background:
- Beta-elemene (β-ELE), derived from Curcuma wenyujin, exhibits anticancer effects in non-small cell lung cancer (NSCLC).
- The precise molecular targets and mechanisms of β-ELE, particularly its role in ferroptosis, remain unclear.
- TFEB regulates lysosome biogenesis, while ferroptosis can be induced by suppressing GPX4; the interplay between TFEB, GPX4, and β-ELE is not well understood.
Purpose of the Study:
- To investigate the interaction between β-ELE and TFEB.
- To elucidate the role of TFEB-mediated GPX4 degradation in β-ELE-induced ferroptosis.
Main Methods:
- Surface plasmon resonance (SPR) and molecular docking were used to assess β-ELE's binding affinity to TFEB.
- Immunofluorescence, western blot, flow cytometry, and qPCR were employed to analyze TFEB and lysosome activation.
- Ferroptosis was evaluated using lipid ROS, labile iron pool (LIP) assays, and western blot; CRISPR/Cas9 was used to create TFEB knockout cells for further mechanistic studies in vitro and in vivo.
Main Results:
- β-ELE directly binds to TFEB, activating TFEB, lysosomal activity, and downstream genes (GLA, MCOLN1, SLC26A11) in EGFR wild-type NSCLC cells.
- β-ELE enhances GPX4 ubiquitination and lysosomal localization, leading to increased GPX4 degradation and subsequent ferroptosis.
- TFEB activation promotes β-ELE-induced ferroptosis, while TFEB knockout significantly compromises this effect, as confirmed in an orthotopic mouse model.
Conclusions:
- This study demonstrates that TFEB-mediated lysosomal degradation of GPX4 is a key mechanism underlying β-ELE-induced ferroptosis in EGFR wild-type NSCLC.
- Targeting TFEB-mediated GPX4 degradation presents a novel therapeutic strategy for inducing ferroptosis and treating NSCLC.
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