title: Mimulone-induced autophagy through p53-mediated AMPK/mTOR pathway increases caspase-mediated apoptotic cell death in A549 human lung cancer cells.
abstract: Anticancer properties and mechanisms of mimulone (MML), C-geranylflavonoid isolated from the Paulownia tomentosa fruits, were firstly elucidated in this study. MML prevented cell proliferation in a dose- and time-dependent way and triggered apoptosis through the extrinsic pathway in A549 human lung adenocarcinoma cells. Furthermore, MML-treated cells displayed autophagic features, such as the formation of autophagic vacuoles, a primary morphological feature of autophagy, and the accumulation of microtubule-associated protein 1 light chain 3 (LC3) puncta, another typical maker of autophagy, as determined by FITC-conjugated immunostaining and monodansylcadaverine (MDC) staining, respectively. The expression levels of LC3-I and LC3-II, specific markers of autophagy, were also augmented by MML treatment. Autophagy inhibition by 3-methyladenine (3-MA), pharmacological autophagy inhibitor, and shRNA knockdown of Beclin-1 reduced apoptotic cell death induced by MML. Autophagic flux was not significantly affected by MML treatment and lysosomal inhibitor, chloroquine (CQ) suppressed MML-induced autophagy and apoptosis. MML-induced autophagy was promoted by decreases in p53 and p-mTOR levels and increase of p-AMPK. Moreover, inhibition of p53 transactivation by pifithrin-α (PFT-α) and knockdown of p53 enhanced induction of autophagy and finally promoted apoptotic cell death. Overall, the results demonstrate that autophagy contributes to the cytotoxicity of MML in cancer cells harboring wild-type p53. This study strongly suggests that MML is a potential candidate for an anticancer agent targeting both autophagy and apoptotic cell death in human lung cancer. Moreover, co-treatment of MML and p53 inhibitor would be more effective in human lung cancer therapy.
authors.affiliation: College of Natural Resources and Life Science, Dong-A University, Busan, 604-714, South Korea.
authors.forename: Hyun-Kyu
authors.initials: HK
authors.lastname: An
authors.affiliation: College of Natural Resources and Life Science, Dong-A University, Busan, 604-714, South Korea.
authors.forename: Kyoung-Sook
authors.initials: KS
authors.lastname: Kim
authors.affiliation: College of Natural Resources and Life Science, Dong-A University, Busan, 604-714, South Korea.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: College of Natural Resources and Life Science, Dong-A University, Busan, 604-714, South Korea.
authors.forename: Mi-Hyun
authors.initials: MH
authors.lastname: Park
authors.affiliation: College of Natural Resources and Life Science, Dong-A University, Busan, 604-714, South Korea.
authors.forename: Hyung-In
authors.initials: HI
authors.lastname: Moon
authors.affiliation: College of Natural Resources and Life Science, Dong-A University, Busan, 604-714, South Korea.
authors.forename: Shin-Ji
authors.initials: SJ
authors.lastname: Park
authors.affiliation: College of Natural Resources and Life Science, Dong-A University, Busan, 604-714, South Korea.
authors.forename: Ji-Sue
authors.initials: JS
authors.lastname: Baik
authors.affiliation: Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, SungKyunKwan University, Kyunggi-Do, 440-746, South Korea.
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
authors.affiliation: College of Natural Resources and Life Science, Dong-A University, Busan, 604-714, South Korea.
authors.forename: Young-Choon
authors.initials: YC
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000230:Adenocarcinoma / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D052160:Benzothiazoles; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D044950:Flavanones / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D000068378:Lamiales / Q000737:chemistry; D008175:Lung Neoplasms / Q000473:pathology*; D061986:MCF-7 Cells; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D052160:Benzothiazoles; D044950:Flavanones; D016159:Tumor Suppressor Protein p53; C000597872:mimulone; D014050:Toluene; C121565:pifithrin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases