title: Metformin inhibits age-related centrosome amplification in Drosophila midgut stem cells through AKT/TOR pathway.
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.
authors.affiliation: Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Na
authors.affiliation: Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea.
authors.forename: Joung-Sun
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea.
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Pyo
authors.affiliation: Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea.
authors.forename: Ho-Jun
authors.initials: HJ
authors.lastname: Jeon
authors.affiliation: Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea.
authors.forename: Young-Shin
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Arking
authors.affiliation: Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea. Electronic address: mayoo@pusan.ac.kr.
authors.forename: Mi-Ae
authors.initials: MA
authors.lastname: Yoo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D016922:Cellular Senescence; D018385:Centrosome / Q000378:metabolism* / Q000648:ultrastructure; D004249:DNA Damage; D015536:Down-Regulation; D004330:Drosophila / Q000378:metabolism*; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007422:Intestines / Q000187:drug effects; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D018384:Oxidative Stress; D010269:Paraquat / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D049452:Green Fluorescent Proteins; D008687:Metformin; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D010269:Paraquat
keywords: AKT/TOR pathway; Centrosome amplification; DNA damage; Drosophila intestinal stem cells (ISCs); Metformin