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Phytosesquiterpene lactones deregulate mitochondrial activity and phenotypes associated with triple-negative breast
Yu-Ting Cheng1, Dao-Ming Chang2, Yi-Chung Tung2
1Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan; Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan; Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan.
Background:
Triple-negative breast cancer (TNBC) recurrence and metastasis are the major causes of failure in TNBC therapy. The difficulties in treating TNBCs may be because of increased cancer cell plasticity that involves the fine-tuning of cellular redox homeostasis, mitochondrial bioenergetics, metabolic characteristics, and the development of cancer stem cells (CSCs).
Purpose:
To investigate the effects and the underlying mechanisms of the phytosesquiterpene lactone deoxyelephantopin (DET) and its semi-synthesized derivative (DETD-35) in suppressing different phenotypic TNBC cell populations that contribute to tumor metastasis.
Methods:
A timelapse microfluidic-based system was established to analyze the effects of DETD-35 and DET on cell migration behavior in an oxygen gradient. Seahorse real-time cell metabolic analyzer and gas chromatography/quadrupole-time-of-flight mass spectrometry (GC/Q-TOF MS) were utilized to analyze the effects of the compounds on mitochondrial bioenergetics in TNBC cells. A miRNA knockout technique and miRNA sponges were employed to evaluate the miR-4284 involvement in the anti-TNBC cell effect of either compound.
Results:
DETD-35 and DET attenuated TNBC cell migration toward hypoxic regions under a 2-19 % oxygen gradient in a timelapse microfluidic-based system. DETD-35 and DET also suppressed CSC-like phenotypes, including the expression of Sox2, Oct4, and CD44 in TNBC cells under hypoxic conditions. DETD-35 and DET affected mitochondrial basal respiration, ATP production, proton leak, and primary metabolism, including glycolysis, the TCA cycle, and amino acid metabolism in the lung-metastatic TNBC cells. Furthermore, the expression of mitophagy markers PARKIN, BNIP3, PINK1, LC3-II, and apoptotic markers Bax, cleaved caspase 7, and cleaved PARP in hypoxic and lung-metastatic TNBC cells was also regulated by treatment with either compound. In miR-4284 knockout cells or miR-4284 inhibitor co-treated TNBC cells, DET- and DETD-35-induced over-expression of mitophagic and apoptotic markers was partially reversed, indicating miR-4284 involved with the compounds caused programmed cell death.
Conclusion:
This study demonstrated the novel activities of DETD-35 and DET in suppressing CSC-like phenotypes and metastatic TNBC cells through the de-regulation of mitochondrial bioenergetics.
Insights
Phytosesquiterpene lactones deoxyelephantopin (DET) and DETD-35 suppress triple-negative breast cancer (TNBC) cell migration and stem-like properties. These compounds target mitochondrial bioenergetics and metabolism, offering potential therapeutic strategies for TNBC metastasis.
Area of Science:
- Molecular Biology
- Cancer Research
- Metabolomics
Background:
- Triple-negative breast cancer (TNBC) recurrence and metastasis are primary challenges in therapy, potentially linked to cancer cell plasticity, redox homeostasis, mitochondrial function, metabolism, and cancer stem cells (CSCs).
- Understanding the mechanisms driving TNBC metastasis is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the anti-metastatic effects of deoxyelephantopin (DET) and its derivative DETD-35 on TNBC.
- To elucidate the underlying mechanisms, focusing on phenotypic suppression and mitochondrial bioenergetics.
Main Methods:
- Utilized a microfluidic system to assess cell migration under oxygen gradients.
- Employed Seahorse analysis and GC/Q-TOF MS to evaluate mitochondrial bioenergetics and metabolism.
- Investigated the role of miR-4284 using knockout and sponge techniques.
Main Results:
- DET and DETD-35 inhibited TNBC cell migration towards hypoxia and suppressed CSC-like phenotypes (Sox2, Oct4, CD44).
- Compounds modulated mitochondrial respiration, ATP production, glycolysis, TCA cycle, and amino acid metabolism.
- Regulated mitophagy and apoptosis markers (PARKIN, BNIP3, PINK1, LC3-II, Bax, cleaved caspase 7, cleaved PARP), with miR-4284 involvement in programmed cell death.
Conclusions:
- DETD-35 and DET exhibit novel activities against metastatic TNBC.
- Suppression of CSC-like phenotypes and metastasis is achieved by de-regulating mitochondrial bioenergetics.
