Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells.
Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC) cells both in vitro and in vivo was demonstrated. However, the mechanism...
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2014
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oai:doaj.org-article:8b7dfc3009114d2ea2a0225d1fa21e6d2021-11-18T08:19:58ZInhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells.1932-620310.1371/journal.pone.0095970https://doaj.org/article/8b7dfc3009114d2ea2a0225d1fa21e6d2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24816744/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC) cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH) likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0-10 µM), comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS) formation. Impact on apoptosis induction and cell function of PHH was analyzed. Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis.Johannes KloseMetodi V StankovMoritz KleineWolf RamackersDiana Panayotova-DimitrovaMark D JägerJürgen KlempnauerMichael WinklerHüseyin BektasGeorg M N BehrensFlorian W R VondranPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 5, p e95970 (2014) |
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Medicine R Science Q |
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Medicine R Science Q Johannes Klose Metodi V Stankov Moritz Kleine Wolf Ramackers Diana Panayotova-Dimitrova Mark D Jäger Jürgen Klempnauer Michael Winkler Hüseyin Bektas Georg M N Behrens Florian W R Vondran Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells. |
| description |
Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC) cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH) likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0-10 µM), comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS) formation. Impact on apoptosis induction and cell function of PHH was analyzed. Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis. |
| format |
article |
| author |
Johannes Klose Metodi V Stankov Moritz Kleine Wolf Ramackers Diana Panayotova-Dimitrova Mark D Jäger Jürgen Klempnauer Michael Winkler Hüseyin Bektas Georg M N Behrens Florian W R Vondran |
| author_facet |
Johannes Klose Metodi V Stankov Moritz Kleine Wolf Ramackers Diana Panayotova-Dimitrova Mark D Jäger Jürgen Klempnauer Michael Winkler Hüseyin Bektas Georg M N Behrens Florian W R Vondran |
| author_sort |
Johannes Klose |
| title |
Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells. |
| title_short |
Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells. |
| title_full |
Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells. |
| title_fullStr |
Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells. |
| title_full_unstemmed |
Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells. |
| title_sort |
inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/8b7dfc3009114d2ea2a0225d1fa21e6d |
| work_keys_str_mv |
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