title: A novel protoapigenone analog RY10-4 induces breast cancer MCF-7 cell death through autophagy via the Akt/mTOR pathway.
abstract: Protoapigenone is a unique flavonoid and enriched in many ferns, showing potent antitumor activity against a broad spectrum of human cancer cell lines. RY10-4, a modified version of protoapigenone, manifested better anti-proliferation activity in human breast cancer cell line MCF-7. The cytotoxicity of RY10-4 against MCF-7 cells is exhibited in both time- and concentration-dependent manners. Here we investigated a novel effect of RY10-4 mediated autophagy in autophagy defect MCF-7 cells. Employing immunofluorescence assay for microtubule-associated protein light-chain 3 (LC3), monodansylcadaverine staining, Western blotting analyses for LC3 and p62 as well as ultrastructural analysis by transmission electron microscopy, we showed that RY10-4 induced autophagy in MCF-7 cells but protoapigenone did not. Meanwhile, inhibition of autophagy by pharmacological and genetic approaches significantly increased the viability of RY10-4 treated cells, suggesting that the autophagy induced by RY10-4 played as a promotion mechanism for cell death. Further studies revealed that RY10-4 suppressed the activation of mTOR and p70S6K via the Akt/mTOR pathway. Our results provided new insights for the mechanism of RY10-4 induced cell death and the cause of RY10-4 showing better antitumor activity than protoapigenone, and supported further evidences for RY10-4 as a lead to design a promising antitumor agent.
authors.affiliation: Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation of Hubei Province, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xuenong
authors.initials: X
authors.lastname: Zhang
authors.forename: Han
authors.initials: H
authors.lastname: Wei
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Liu
authors.forename: Qianying
authors.initials: Q
authors.lastname: Yuan
authors.forename: Anhua
authors.initials: A
authors.lastname: Wei
authors.forename: Du
authors.initials: D
authors.lastname: Shi
authors.forename: Xian
authors.initials: X
authors.lastname: Yang
authors.forename: Jinlan
authors.initials: J
authors.lastname: Ruan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000208:ethnology* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D046529:Microscopy, Electron, Transmission; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C574037:2-(1-hydroxy-4-oxocyclohexa-2,5-dienyl)pyran-4-one; D000970:Antineoplastic Agents; D011753:Pyrones; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases