title: Zapotin (5,6,2',6'-tetramethoxyflavone) Modulates the Crosstalk Between Autophagy and Apoptosis Pathways in Cancer Cells with Overexpressed Constitutively Active PKCϵ.
abstract: Autophagy is important in the regulation of survival and death signaling pathways in cancer. PKCϵ revealed high transforming potential and the ability to increase cell migration, invasion, and metastasis. Zapotin (5,6,2',6'-tetramethoxyflavone), a natural flavonoid, showed chemopreventive and anticancer properties. Previously, we reported that downmodulation of induced PKCϵ level by zapotin was associated with decreased migration and increased apoptosis in HeLa cell line containing doxycycline-inducible constitutively active PKCϵ (PKCϵA/E, Ala(159) → Glu). Depending on the genetic and environmental content of cells, autophagy may either precede apoptosis or occur simultaneously. The purpose of this study was to assess the effect of zapotin on autophagy. Increasing concentration of zapotin (from 7.5 µM to 30 µM) caused an inhibition of the formation of autophagosomes and a decline in microtubule-associated protein 1 light chain 3 (LC3) protein levels. The gene expression level of major negative regulator of autophagy was noticeably increased. Moreover, the expression of the pivotal autophagy genes was decreased. These changes were accompanied by alternation in autophagy-related protein levels. In conclusion, our results implied that both the antiautophagic and the proapoptosis effect of zapotin in HeLaPKCϵA/E cells are associated with the protein kinase C epsilon signaling pathway and lead to programmed cell death.
authors: a Department of Clinical Chemistry and Molecular Diagnostics , Poznan University of Medical Sciences , Poznan , Poland.
authors: Ewa
authors: E
authors: Toton
authors: a Department of Clinical Chemistry and Molecular Diagnostics , Poznan University of Medical Sciences , Poznan , Poland.
authors: Aleksandra
authors: A
authors: Romaniuk
authors: b Department of Pharmaceutical Botany , Poznan University of Medical Sciences , Poznan , Poland.
authors: Jaromir
authors: J
authors: Budzianowski
authors: c Biocenter, Division of Medical Biochemistry, Innsbruck Medical University , Innsbruck , Austria.
authors: Johann
authors: J
authors: Hofmann
authors: a Department of Clinical Chemistry and Molecular Diagnostics , Poznan University of Medical Sciences , Poznan , Poland.
authors: Maria
authors: M
authors: Rybczynska
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D047309:Flavones / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047309:Flavones; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C517807:zapotin; D051744:Protein Kinase C-epsilon; D004318:Doxycycline