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Metformin inhibits age-related centrosome amplification in Drosophila midgut stem cells through AKT/TOR pathway
Hyun-Jin Na1, Joung-Sun Park1, Jung-Hoon Pyo1
1Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea.
Abstract:
We delineated the mechanism regulating the inhibition of centrosome amplification by metformin in Drosophila intestinal stem cells (ISCs). Age-related changes in tissue-resident stem cells may be closely associated with tissue aging and age-related diseases, such as cancer. Centrosome amplification is a hallmark of cancers. Our recent work showed that Drosophila ISCs are an excellent model for stem cell studies evaluating age-related increase in centrosome amplification. Here, we showed that metformin, a recognized anti-cancer drug, inhibits age- and oxidative stress-induced centrosome amplification in ISCs. Furthermore, we revealed that this effect is mediated via down-regulation of AKT/target of rapamycin (TOR) activity, suggesting that metformin prevents centrosome amplification by inhibiting the TOR signaling pathway. Additionally, AKT/TOR signaling hyperactivation and metformin treatment indicated a strong correlation between DNA damage accumulation and centrosome amplification in ISCs, suggesting that DNA damage might mediate centrosome amplification. Our study reveals the beneficial and protective effects of metformin on centrosome amplification via AKT/TOR signaling modulation. We identified a new target for the inhibition of age- and oxidative stress-induced centrosome amplification. We propose that the Drosophila ISCs may be an excellent model system for in vivo studies evaluating the effects of anti-cancer drugs on tissue-resident stem cell aging.
Insights
Metformin, an anti-cancer drug, inhibits centrosome amplification in aging Drosophila stem cells by down-regulating AKT/target of rapamycin (TOR) signaling. This suggests a new therapeutic strategy for age-related diseases and cancer prevention.
Area of Science:
- Stem cell biology
- Aging research
- Cancer biology
Background:
- Age-related stem cell dysfunction contributes to aging and diseases like cancer.
- Centrosome amplification is a key feature of cancer.
- Drosophila intestinal stem cells (ISCs) serve as a model for studying age-related centrosome amplification.
Purpose of the Study:
- To elucidate the mechanism by which metformin inhibits centrosome amplification in Drosophila ISCs.
- To investigate the role of AKT/TOR signaling in metformin's effect.
- To explore the link between DNA damage and centrosome amplification.
Main Methods:
- Utilized Drosophila intestinal stem cells (ISCs) as a model system.
- Administered metformin to assess its effects on centrosome amplification.
- Analyzed the AKT/TOR signaling pathway activity.
- Investigated the correlation between DNA damage and centrosome amplification.
Main Results:
- Metformin effectively inhibits age- and oxidative stress-induced centrosome amplification in ISCs.
- This inhibition is mediated by the down-regulation of AKT/target of rapamycin (TOR) signaling.
- A strong correlation was observed between DNA damage accumulation and centrosome amplification, suggesting a mediating role for DNA damage.
Conclusions:
- Metformin exerts protective effects against centrosome amplification by modulating AKT/TOR signaling.
- This study identifies a novel target for inhibiting age- and oxidative stress-induced centrosome amplification.
- Drosophila ISCs are a valuable model for in vivo evaluation of anti-cancer drugs targeting stem cell aging.
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