Journal
ONCOTARGET
Volume 8, Issue 53, Pages 91402-91414Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20592
Keywords
hepatocarcinoma; hypoxia-inducible factor-1 alpha; hypoxia-mediated mitophagy; melatonin; sorafenib
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Funding
- Instituto de Salud Carlos III, Spain
- Ministry of Education of Spain (Becas FPU) [FPU13/04173, FPU16/05277]
- Asociacion Espanola Contra el Cancer (AEEC)-Junta provincial de Leon
- Consejeria de Educacion
- Fondo Social Europeo - FEDER - [LE063U16]
- Junta de Castilla y Leon
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The antiangiogenic effects of sustained sorafenib treatment in hepatocellular carcinoma (HCC) lead to the occurrence of hypoxia-mediated drug resistance resulting in low therapy efficiency and negative outcomes. Combined treatments with coadjuvant compounds to target the hypoxia-inducible factor-1 alpha (HIF-1 alpha) represent a promising therapeutic approach through which sorafenib efficiency may be improved. Melatonin is a well-documented oncostatic agent against different cancer types. Here, we evaluated whether melatonin could enhance sorafenib cytotoxicity and overcome the hypoxia-mediated resistance mechanisms in HCC. The pharmacological melatonin concentration (2 mM) potentiated the oncostatic effects of sorafenib (5 mu M) on Hep3B cells even under hypoxia. Melatonin downregulated the HIF-1 alpha protein synthesis through the inhibition of the mammalian target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase beta-1 (p70S6K)/ribosomal protein S6 (RP-S6) pathway, although the indole enhanced Akt phosphorylation by the mTORC1/C2 negative feedback. Furthermore, melatonin and sorafenib coadministration reduced the HIF1 alpha-mitophagy targets expression, impaired autophagosome formation and subsequent mitochondria and lysosomes colocalization. Together, our results indicate that melatonin improves the Hep3B sensitivity to sorafenib, preventing HIF-1 alpha synthesis to block the cytoprotective mitophagy induced by the hypoxic microenvironment, an important element of the multifactorial mechanisms responsible for the chemotherapy failure.
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