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Efflux inhibition by H2S confers sensitivity to doxorubicin-induced cell death in liver cancer cells
- Source :
- Life Sciences. 213:116-125
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Aims Hydrogen sulfide (H2S), an important gasotransmitter, is involved in a variety of cellular functions and pathophysiologic processes. Drug resistance due to alterations in drug trafficking and metabolism severely limits the effectiveness of cancer therapy. This study examined the role of H2S in drug resistance in liver cancer cells. Materials and methods Human primary hepatocellular carcinoma cell line (HepG2) and doxorubicin (Dox)-resistant cells were used in this study. Cell survival was analyzed by MTT, Annexin V-FITC/propidium iodide staining and clonogenic assay. Western blotting was used for analysis of protein expression, and immunoprecipitation was used to determine interactions of LXR/RXR. Key findings The expression of H2S-generating enzyme cystathionine gamma-lyase (CSE) was inhibited by doxorubicin treatment in HepG2 cells, and H2S sensitized Dox-inhibited cell survival and colony formation. In addition, H2S promoted cellular retention of Dox by suppressing the expressions of ABCA1 and ABCG8. H2S significantly blocked Dox-induced heterodimer formation between LXRα and RXRβ and attenuated the binding of LXRα/RXRβ to the promoters of ABCA1 and ABCG8 genes. RXRβ but not LXRα was S-sulfhydrated by H2S, and blockage of RXRβ S-sulfhydration abolished the inhibitory role of H2S on LXRα/RXRβ heterodimer formation. CSE expression was reduced in Dox-resistant cells in comparison with their parental cells, while H2S could reverse drug resistance in Dox-resistant cells. Significance Our study provides a novel solution for reversing drug resistance in cancer cells by targeting H2S signalling.
- Subjects :
- 0301 basic medicine
Programmed cell death
Chemistry
General Medicine
equipment and supplies
General Biochemistry, Genetics and Molecular Biology
3. Good health
Blot
03 medical and health sciences
chemistry.chemical_compound
030104 developmental biology
0302 clinical medicine
Annexin
030220 oncology & carcinogenesis
Cancer cell
polycyclic compounds
medicine
Cancer research
Doxorubicin
Propidium iodide
General Pharmacology, Toxicology and Pharmaceutics
Liver X receptor
Clonogenic assay
medicine.drug
Subjects
Details
- ISSN :
- 00243205
- Volume :
- 213
- Database :
- OpenAIRE
- Journal :
- Life Sciences
- Accession number :
- edsair.doi...........c2140c7ac982fa1c37a6731c02daf441