Abstract
Despite sorafenib effectiveness against advanced hepatocarcinoma (HCC), long-term exposure to antiangiogenic drugs leads to hypoxic microenvironment, a key contributor to chemoresistance acquisition. We aimed to study the role of hypoxia in the development of sorafenib resistance in a human HCC in vitro model employing the HCC line HepG2 and two variants with acquired sorafenib resistance, HepG2S1 and HepG2S3, and CoCl2 as hypoximimetic. Resistant cells exhibited a faster proliferative rate and hypoxia adaptive mechanisms, linked to the increased protein levels and nuclear translocation of hypoxia-inducible factors (HIFs). HIF-1α and HIF-2α overexpression was detected even under normoxia through a deregulation of its degradation mechanisms. Proapoptotic markers expression and subG1 population decreased significantly in HepG2S1 and HepG2S3, suggesting evasion of sorafenib-mediated cell death. HIF-1α and HIF-2α knockdown diminished resistant cells viability, relating HIFs overexpression with its prosurvival ability. Additionally, epigenetic silencing of Bcl-2 interacting protein 3 (BNIP3) was observed in sorafenib resistant cells under hypoxia. Demethylation of BNIP3 promoter, but not histone acetylation, restored BNIP3 expression, driving resistant cells’ death. Altogether, our results highlight the involvement of HIFs overexpression and BNIP3 methylation-dependent knockdown in the development of sorafenib resistance in HCC. Targeting both prosurvival mechanisms could overcome chemoresistance and improve future therapeutic approaches.
Highlights
Hepatocarcinoma (HCC), a common malignancy worldwide with a quick rise in incidence, is one of the main causes of cancer-related death because of its high mortality rate [1]
The results obtained from the sorafenib hepatocellular carcinoma assessment randomized protocol (SHARP) clinical trial showed that this drug is effective and safe, encouraging the approval of sorafenib for advanced HCC [1]
The interplay between the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, disabling apoptotic signals, dysregulation of cell cycle control, epigenetic regulation, epithelial–mesenchymal transition and the hypoxia-inducible response are some of the mechanisms involved in the cells sensitivity to sorafenib decline [2]
Summary
Hepatocarcinoma (HCC), a common malignancy worldwide with a quick rise in incidence, is one of the main causes of cancer-related death because of its high mortality rate [1]. Cancers 2019, 11, 1984 the first-line therapy employed is the palliative treatment with sorafenib (BAY 43-9006, Nexavar® ), an oral multikinase inhibitor with antiproliferative, proapoptotic, and antiangiogenic properties [2]. B-Raf, with the consequent inhibition of the mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK) signaling pathway. The proapoptotic action of the drug is associated with the inhibition of eIF4E phosphorylation and subsequent downregulation of the antiapoptotic factor induced myeloid leukemia cell differentiation protein (Mcl-1) translation [1,3]. The interplay between the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, disabling apoptotic signals, dysregulation of cell cycle control, epigenetic regulation, epithelial–mesenchymal transition and the hypoxia-inducible response are some of the mechanisms involved in the cells sensitivity to sorafenib decline [2]
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