Inhibition of AMPK-associated autophagy enhances caffeic acid phenethyl ester-induced cell death in C6 glioma cells

Szu Hsu Yu, Yung Ta Kao, Jui Yu Wu, Shih Hao Huang, Sheng Tung Huang, Chi-Ming Lee, Kur Ta Cheng, Chun Mao Lin

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

An increasing number of studies show that AMP-activated protein kinase (AMPK) activation can inhibit apoptosis. To clarify the antitumor mechanism of caffeic acid phenethyl ester (CAPE) and achieve increased therapeutic efficiency, we investigated the potential roles of AMPK and autophagy in CAPE treatment against C6 glioma cells. The roles of AMPK and autophagy inhibition in CAPE's cytotoxic action were investigated. Phosphorylation of AMPK and mitogen-activated protein kinases (MAPKs) were observed in tumor cells following CAPE treatment. A combination of CAPE and the AMPK inhibitor, compound C, resulted in augmented cell death. Similar effects of compound C were observed in response to changes in the mitochondrial membrane potential (Δψm). Small interfering RNA-mediated AMPK downregulation increased CAPE-induced cell death. The results suggest that AMPK activation plays a role in diminishing apoptosis. CAPE treatment induced an increase in LC3 conversion as represented by the LC3-II/LC3-I ratio. Enlarged lysosomes and autophagosomes were present according to electron microscopy. The autophagy inhibitor, 3-MA, caused increased CAPE cytotoxicity, which suggests that autophagy induction protected glioma cells from CAPE. The combination of CAPE with autophagy and AMPK inhibitors markedly enhanced the cytotoxicity toward C6 glioma cells. Accordingly, CAPE-triggered activation of AMPK and the autophagic response protected tumor cells from apoptotic death. This provides new insights for combined therapy to enhance the therapeutic potential of cancer treatments.

Original languageEnglish
Pages (from-to)907-914
Number of pages8
JournalPlanta Medica
Volume77
Issue number9
DOIs
Publication statusPublished - 2011

Keywords

  • AMPK
  • autophagy
  • CAPE
  • glioma
  • oxidative stress

ASJC Scopus subject areas

  • Complementary and alternative medicine
  • Molecular Medicine
  • Organic Chemistry
  • Analytical Chemistry
  • Pharmaceutical Science
  • Pharmacology
  • Drug Discovery

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