Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells.

Autor: Méndez-Blanco C; Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 León, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029 Madrid, Spain., Fondevila F; Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 León, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029 Madrid, Spain., Fernández-Palanca P; Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 León, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029 Madrid, Spain., García-Palomo A; Service of Oncology, Complejo Asistencial Universitario de León, Calle Altos de Nava, s/n, 24001 León, Spain., Pelt JV; Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven and University Hospitals Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., Verslype C; Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven and University Hospitals Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium., González-Gallego J; Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 León, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029 Madrid, Spain., Mauriz JL; Institute of Biomedicine (IBIOMED), University of León, Campus of Vegazana s/n, 24071 León, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Av. de Monforte de Lemos, 5, 28029 Madrid, Spain.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2019 Dec 09; Vol. 11 (12). Date of Electronic Publication: 2019 Dec 09.
DOI: 10.3390/cancers11121984
Abstrakt: 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 CoCl 2 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.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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