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Human menstrual blood-derived stem cells reverse sorafenib resistance in hepatocellular carcinoma cells through the hyperactivation of mitophagy.
- Source :
-
Stem cell research & therapy [Stem Cell Res Ther] 2023 Apr 01; Vol. 14 (1), pp. 58. Date of Electronic Publication: 2023 Apr 01. - Publication Year :
- 2023
-
Abstract
- Background: Sorafenib is a first-line drug targeting the RTK-MAPK signalling pathway used to treat advanced hepatocellular carcinoma (HCC). However, tumour cells readily develop sorafenib resistance, limiting long-term therapy with this drug. In our previous study, we found that human menstrual blood-derived stem cells (MenSCs) altered the expression of some sorafenib resistance-associated genes in HCC cells. Therefore, we wanted to further explore the feasibility of MenSC-based combination therapy in treating sorafenib-resistant HCC (HCC-SR) cells.<br />Methods: The therapeutic efficiency of sorafenib was determined using CCK-8 (Cell Counting Kit-8), Annexin V/PI and clone formation assays in vitro and a xenograft mouse model in vivo. DNA methylation was determined using RT‒PCR and methylated DNA immunoprecipitation (MeDIP). Autophagy was detected by measuring LC3-II degradation and autophagosome maturation. Transmission electron microscopy identified autophagosomes and mitochondria. Physiological functions of mitochondria were assessed by measuring the ATP content, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP).<br />Results: The tumour suppressor genes BCL2 interacting protein 3 (BNIP3) and BCL2 interacting protein 3 like (BNIP3L) were silenced by promoter methylation and that BNIP3 and BNIP3L levels correlated negatively with sorafenib resistance in HCC-SR cells. Strikingly, MenSCs reversed sorafenib resistance. MenSCs upregulated BNIP3 and BNIP3L expression in HCC-SR cells via tet methylcytosine dioxygenase 2 (TET2)-mediated active demethylation. In HCC-SR cells receiving sorafenib and MenSC combination therapy, pressure from sorafenib and elevated BNIP3 and BNIP3L levels disrupted balanced autophagy. Hyperactivation of mitophagy significantly caused severe mitochondrial dysfunction and eventually led to the autophagic death of HCC-SR cells.<br />Conclusions: Our research suggests that combining sorafenib and MenSCs may be a potentially new strategy to reverse sorafenib resistance in HCC-SR cells.<br /> (© 2023. The Author(s).)
- Subjects :
- Humans
Animals
Mice
Sorafenib pharmacology
Sorafenib therapeutic use
Mitophagy genetics
Stem Cells pathology
Proto-Oncogene Proteins c-bcl-2
Cell Line, Tumor
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular genetics
Carcinoma, Hepatocellular pathology
Liver Neoplasms drug therapy
Liver Neoplasms genetics
Liver Neoplasms pathology
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1757-6512
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Stem cell research & therapy
- Publication Type :
- Academic Journal
- Accession number :
- 37005657
- Full Text :
- https://doi.org/10.1186/s13287-023-03278-8