The role of hydrogen sulfide in doxorubicin-induced drug resistance in hepatocellular carcinoma cells
Date
2018-09-17
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Abstract
Doxorubicin is one of the most common chemical agents used in the treatment of cancers.
Doxorubicin-treated cancer cells often develop drug resistance due to alterations in the
trafficking and metabolism of the drug, which severely limits the drug’s effectiveness. This is
seen at especially high rates in human hepatocellular carcinoma (HCC), the most common form
of liver cancer. H2S is an important gasotransmitter and is involved in a variety of cellular
functions and pathophysiologic processes. The role of H2S in drug resistance in cancer cells is
still unclear. In this study, by using a human hepatocellular carcinoma cell line (HepG2), we
found that NaHS (an H2S donor) was able to reduce cancer cell viability and colony formation in
a doxorubicin dose dependent manner, while H2S alone did not show any effect. The expression
of H2S-generating enzyme cystathionine gamma-lyase (CSE) but not cystathionine beta-synthase
(CBS) was reduced by doxorubicin treatment. In addition, H2S promoted cellular retention of
doxorubicin in HepG2 cells, possibly by suppressing the expression of ABCA1 and ABCG8, two
drug efflux proteins. LXRα acts as a transcription factor for ABCA1 and ABCG8, however our
findings showed that H2S had no effect on the protein expression and S-sulfhydration of LXRα,
suggesting LXRα is not involved in H2S-regulated expressions of ABCA1 and ABCG8. In
comparison with the parental cells, CSE expression was also reduced in doxorubicin-resistant
cells. Exogenously applied NaHS reversed the drug resistance in doxorubicin-resistant cells. In
conclusion, our study provides a novel solution for reversing drug resistance by targeting H2S
signaling.
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Keywords
H2S, Cystathionine gamma-lyase, human hepatocellular carcinoma, doxorubicin, drug resistance