International journal of molecular sciences, 2017-05, Vol.18 (5), p.1088
2017
Details
- Autor(en) / Beteiligte
- Titel
- Inhibition of Autophagy Promotes Salinomycin-Induced Apoptosis via Reactive Oxygen Species-Mediated PI3K/AKT/mTOR and ERK/p38 MAPK-Dependent Signaling in Human Prostate Cancer Cells
- Ist Teil von
- International journal of molecular sciences, 2017-05, Vol.18 (5), p.1088
- Ort / Verlag
- Switzerland: MDPI AG
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
- Beschreibungen/Notizen
- Recently, the interplay between autophagy and apoptosis has become an important factor in chemotherapy for cancer treatment. Inhibition of autophagy may be an effective strategy to improve the treatment of chemo-resistant cancer by consistent exposure to chemotherapeutic drugs. However, no reports have clearly elucidated the underlying mechanisms. Therefore, in this study, we assessed whether salinomycin, a promising anticancer drug, induces apoptosis and elucidated potential antitumor mechanisms in chemo-resistant prostate cancer cells. Cell viability assay, Western blot, annexin V/propidium iodide assay, acridine orange (AO) staining, caspase-3 activity assay, reactive oxygen species (ROS) production, and mitochondrial membrane potential were assayed. Our data showed that salinomycin alters the sensitivity of prostate cancer cells to autophagy. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, enhanced the salinomycin-induced apoptosis. Notably, salinomycin decreased phosphorylated of AKT and phosphorylated mammalian target of rapamycin (mTOR) in prostate cancer cells. Pretreatment with LY294002, an autophagy and PI3K inhibitor, enhanced the salinomycin-induced apoptosis by decreasing the AKT and mTOR activities and suppressing autophagy. However, pretreatment with PD98059 and SB203580, an extracellular signal-regulated kinases (ERK), and p38 inhibitors, suppressed the salinomycin-induced autophagy by reversing the upregulation of ERK and p38. In addition, pretreatment with -acetyl-l-cysteine (NAC), an antioxidant, inhibited salinomycin-induced autophagy by suppressing ROS production. Our results suggested that salinomycin induces apoptosis, which was related to ROS-mediated autophagy through regulation of the PI3K/AKT/mTOR and ERK/p38 MAPK signaling pathways.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1422-0067, 1661-6596eISSN: 1422-0067DOI: 10.3390/ijms18051088Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5454997
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, Acetylcysteine, Acridine orange, AKT protein, Annexin V, Antitumor activity, Apoptosis, Apoptosis - drug effects, Assaying, Autophagy, Autophagy - drug effects, Caspase, Caspase-3, Cell Proliferation - drug effects, Chemotherapy, Cysteine, Drugs, Extracellular signal-regulated kinase, Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors, Extracellular Signal-Regulated MAP Kinases - metabolism, Flavonoids - pharmacology, Humans, Imidazoles - pharmacology, Inhibitors, Male, Mammals, MAP kinase, MAP Kinase Signaling System - drug effects, Membrane potential, Membrane Potential, Mitochondrial - drug effects, Mitochondria, Oxygen, p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors, p38 Mitogen-Activated Protein Kinases - metabolism, Phagocytosis, Phosphatidylinositol 3-Kinases - antagonists & inhibitors, Phosphatidylinositol 3-Kinases - metabolism, Pretreatment, Propidium iodide, Prostate cancer, Proto-Oncogene Proteins c-akt - antagonists & inhibitors, Proto-Oncogene Proteins c-akt - metabolism, Pyrans - pharmacology, Pyridines - pharmacology, Rapamycin, Reactive Oxygen Species - metabolism, Retarding, Salinomycin, Sensitivity, Staining, TOR Serine-Threonine Kinases - antagonists & inhibitors, TOR Serine-Threonine Kinases - metabolism