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Andrographolide Induces Mitochondrial Dysfunction and Alters Stemness-related Gene Expression in MCF7 Breast Cancer
Natthima Suwan1, Sasipat Teerawongsuwan2, Sirinya Jenjittikul1
1Faculty of Medicine, Srinakharinwirot University, Nakhon Nayok, Thailand.
Background/Aim:
Andrographolide, a compound derived from Andrographis paniculata, has exhibited promising antineoplastic effects; however, its effects on pluripotency and cancer stemness remain unclear. Since pluripotency and cancer stemness are key factors in treatment resistance and relapse, it is important to investigate how andrographolide affects these properties.
Materials And Methods:
MCF7 cells were treated with andrographolide (7.5-120 μM) for 24 or 48 h. Cell viability was evaluated using the MTT assay. Mitochondrial membrane potential was measured using TMRE. Gene expression of TOMM20, caspase-3, BAX, BCL2 and OCT4 was analyzed using RT-qPCR. Mammosphere and colony formation assays were performed to assess self-renewal and proliferation.
Results:
MTT assays revealed a dose- and time-dependent reduction in the cell viability following andrographolide treatment. TMRE staining revealed a decrease in the mitochondrial membrane potential of andrographolide-treated MCF7 cells, indicating mitochondrial dysfunction. RT-qPCR analysis showed down-regulation of TOMM20 and caspase-3 expression, although MCF7 cells are typically caspase-3 deficient. Notably, BAX expression was up-regulated following treatment with 60 μM andrographolide, suggesting the induction of apoptosis. A dose-dependent increase in OCT4 expression was observed, with a 13.52-fold rise at 60 μM, indicating a potential shift toward a pluripotent-like state. Gene correlation analysis revealed a negative correlation between TOMM20 and OCT4 expression, suggesting that TOMM20 down-regulation enhances pluripotency. The positive correlation between OCT4 and BAX expression suggests a complex link between apoptosis and stemness. Immunocytochemistry confirmed TOMM20 localization in the cytoplasm. Reduced mammosphere and colony formation indicated decreased self-renewal and proliferation.
Conclusion:
Andrographolide exerts anti-cancer effects through mitochondrial dysfunction and apoptosis, while paradoxically increases OCT4 expression. These findings may indicate an adaptive cellular survival mechanism, in which OCT4 up-regulation and TOMM20 down-regulation are correlated with cancer-like characteristics.
Insights
Andrographolide shows anti-cancer effects by inducing mitochondrial dysfunction and apoptosis. Paradoxically, it increases OCT4 (octamer-binding transcription factor 4) expression, potentially indicating an adaptive survival mechanism in cancer cells.
Area of Science:
- Pharmacology
- Cancer Biology
- Cellular Biology
Background:
- Andrographolide from *Andrographis paniculata* shows anti-cancer potential.
- Its impact on cancer stemness and pluripotency, crucial for treatment resistance, is not well understood.
Purpose of the Study:
- To investigate the effects of andrographolide on cancer cell pluripotency and stemness.
- To elucidate the mechanisms underlying andrographolide's anti-cancer activity.
Main Methods:
- MCF7 cells were treated with varying concentrations of andrographolide.
- Assays included MTT for viability, TMRE for mitochondrial potential, RT-qPCR for gene expression (TOMM20, OCT4, BAX, etc.), and mammosphere/colony formation assays.
Main Results:
- Andrographolide reduced cell viability and mitochondrial membrane potential, indicating dysfunction.
- It upregulated BAX and OCT4 (octamer-binding transcription factor 4) expression, suggesting apoptosis induction and a shift towards pluripotency.
- Reduced mammosphere and colony formation indicated decreased cancer stemness.
Conclusions:
- Andrographolide exhibits anti-cancer properties via mitochondrial dysfunction and apoptosis.
- The observed increase in OCT4 expression suggests a potential adaptive survival response, linked to cancer stem-like characteristics.
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