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

Abstract

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 N-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.

Origanum majorana Essential Oil Triggers p38 MAPK-Mediated Protective Autophagy, Apoptosis, and Caspase-Dependent Cleavage of P70S6K in Colorectal Cancer Cells

“…Also, Salinomycin, a natural compound isolated from Streptomyces albus, was shown to induce p38 MAPK-mediated downregulation of the AKT/mTOR pathway, protective autophagy, and apoptosis in human prostate cancer cells [44]. Inhibition of autophagy with 3-MA enhanced Salinomycine-induced apoptosis and pretreatment with the p38 inhibitor SB 203,580 decreased salinomycin-induced autophagy [44]. Here we showed that OMEO activated both autophagy and apoptosis, with autophagy occurring first.…”

“…Pharmacological inhibition of autophagy by 3-MA increased Resveratrol-induced cell death, while inhibition of p38 MAPK by SB 203,580 exerted the opposite effect [39]. Also, Salinomycin, a natural compound isolated from Streptomyces albus, was shown to induce p38 MAPK-mediated downregulation of the AKT/mTOR pathway, protective autophagy, and apoptosis in human prostate cancer cells [44]. Inhibition of autophagy with 3-MA enhanced Salinomycine-induced apoptosis and pretreatment with the p38 inhibitor SB 203,580 decreased salinomycin-induced autophagy [44].…”

Shikonin induces apoptosis and prosurvival autophagy in human melanoma A375 cells via ROS-mediated ER stress and p38 pathways

“…A study on HT1080 human fibrosarcoma cells showed that Silibinin induces autophagy through the activation of ROS-p38 [12]. Kim et al [38] also confirmed that Salinomycin induced autophagy through regulation of the ROS-mediated p38-MAPK signaling pathway in human prostate cancer cells. Ahn et al [9] reported that Shikonin could activate the p38 MAPK pathway.…”

Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas

“…While several publications have reported that salinomycin suppresses autophagy, 24,25 others have claimed that it induces autophagy. 22,25,26 This controversy may be due to technical differences in the methods used to detect autophagy.…”