Journal
ONCOGENE
Volume 40, Issue 3, Pages 492-507Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-020-01545-z
Keywords
-
Funding
- Research Grants Council of the Hong Kong SAR [CUHK14117015]
Ask authors/readers for more resources
The study revealed that CYP1A2 can sensitize sorafenib-resistant cells to the drug by inhibiting the NF-kappa B p65 axis, thereby increasing drug sensitivity and enhancing the inhibitory effect of the drug.
Sorafenib resistance has become the main obstacle in the effective treatment of advanced hepatocellular carcinoma (HCC) patients. Activation of nuclear factor kappa B (NF-kappa B) is a newly identified mechanism that contributes to desensitized sorafenib. Cytochrome P450 1A2 (CYP1A2) functions as a tumor suppressor in HCC and its expression is negatively associated with NF-kappa B in the liver. This study aimed to study whether CYP1A2 could overcome sorafenib resistance. To investigate whether CYP1A2 and NF-kappa B p65 played roles in sorafenib desensitization, we established sorafenib-resistant (SR) HCC cells. SR cells decreased the expression of CYP1A2 along with the upregulation of NF-kappa B p65. CYP1A2 overexpression attenuated SR cell proliferation, increased sorafenib sensitivity, and inhibited the NF-kappa B pathway, whereas CYP1A2 silence showed opposite effects. Sorafenib, in combination with omeprazole, a CYP1A2 inducer, significantly hindered the growth and invasion of SR cells in vitro as well as decreased the tumor growth in vivo. The combination treatment markedly increased CYP1A2 expression and inhibited the sorafenib-induced NF-kappa B signaling. In addition, the overexpression of NF-kappa B p65 stimulated the SR cell growth and desensitized sorafenib in SR cells, where CYP1A2 overexpression reversed the phenomenon. Lastly, the majority of HCC tissue samples displayed decreased CYP1A2 but increased NF-kappa B p65 protein expression. Collectively, CYP1A2 can sensitize SR cells to sorafenib via inhibiting NF-kappa B p65 axis. Omeprazole in combination with sorafenib exerts a synergistic effect in alleviating acquired sorafenib resistance.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available