Title: New compound ChlA-F induces autophagy-dependent anti-cancer effect via upregulating Sestrin-2 in human bladder cancer.
Authors: Hua, Xiaohui; Xu, Jiheng; Deng, Xu; Xu, Jiawei; Li, Jingxia; Zhu, David Q; Zhu, Junlan; Jin, Honglei; Tian, Zhongxian; Huang, Haishan; Zhao, Qin-Shi; Huang, Chuanshu
Published In Cancer Lett, (2018 11 01)
Abstract: ChlA-F is a novel conformation-derivative of Cheliensisin A, styryl-lactone isolates that show potent anti-tumor potential in vivo and vitro. However, the anti-cancer activity and its potential mechanisms underlying ChlA-F action have never been explored. In the present study, we evaluated the potency of ChlA-F on autophagy-mediated anchorage-independent growth inhibition in human high-grade invasive bladder cancer (BC) cells. We found that ChlA-F treatment significantly inhibited anchorage-independent growth of human BC cells by inducing autophagy in a Sestrin-2 (SESN2)-dependent fashion. Our results revealed that ChlA-F treatment specifically induced SESN2 expression via increasing its transcription and mRNA stability. On one hand, ChlA-F treatment markedly attenuated Dicer protein abundance, in turn abolishing miR-27a maturation and further relieving miR-27a binding directly to SESN2 mRNA 3'UTR, thereby promoting SESN2 mRNA stabilization. On the other hand, ChlA-F treatment promoted Sp1 abundance and consequently mediated SESN2 transcription. These results demonstrate that its activation of the autophagic pathway through specifically promoting SESN2 expression mediates the anti-cancer effect of ChlA-F, which offers insights into the novel anti-cancer effect of ChlA-F on BC, as well as providing therapeutic alternatives against human BC.
PubMed ID: 30118841
MeSH Terms: 3' Untranslated Regions/genetics; Antineoplastic Agents/chemistry; Antineoplastic Agents/pharmacology*; Autophagy/drug effects*; Autophagy/genetics; Cell Line; Cell Line, Tumor; DEAD-box RNA Helicases/genetics; DEAD-box RNA Helicases/metabolism; Epoxy Compounds/chemistry; Epoxy Compounds/pharmacology; Gene Expression Regulation, Neoplastic/drug effects*; Humans; Lactones/chemistry; Lactones/pharmacology*; MicroRNAs/genetics; Molecular Structure; Nuclear Proteins/genetics*; Nuclear Proteins/metabolism; Pyrones/chemistry; Pyrones/pharmacology; RNA Stability/drug effects; RNA Stability/genetics; Ribonuclease III/genetics; Ribonuclease III/metabolism; Up-Regulation/drug effects; Urinary Bladder Neoplasms/drug therapy; Urinary Bladder Neoplasms/genetics*; Urinary Bladder Neoplasms/metabolism