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Cytochrome P450 1A2 overcomes nuclear factor kappa B-mediated sorafenib resistance in hepatocellular carcinoma

Oncogene volume 40, pages 492–507 (2021)Cite this article

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Abstract

Sorafenib resistance has become the main obstacle in the effective treatment of advanced hepatocellular carcinoma (HCC) patients. Activation of nuclear factor kappa B (NF‐κB) 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‐κB in the liver. This study aimed to study whether CYP1A2 could overcome sorafenib resistance. To investigate whether CYP1A2 and NF‐κB 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‐κB p65. CYP1A2 overexpression attenuated SR cell proliferation, increased sorafenib sensitivity, and inhibited the NF‐κB 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‐κB signaling. In addition, the overexpression of NF‐κB 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‐κB p65 protein expression. Collectively, CYP1A2 can sensitize SR cells to sorafenib via inhibiting NF‐κB p65 axis. Omeprazole in combination with sorafenib exerts a synergistic effect in alleviating acquired sorafenib resistance.

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Fig. 1: CYP1A2 inhibits cell growth and sensitizes sorafenib-resistant (SR) PLC/PRF/5 and Huh7 cells to sorafenib.
Fig. 2: Omeprazole in combination with sorafenib inhibits tumor growth in vitro and in vivo.
Fig. 3: Omeprazole-sorafenib combination hinders SR cell growth in vitro.
Fig. 4: Omeprazole suppresses sorafenib-mediated NF‐κB p65 induction.
Fig. 5: CYP1A2 overexpression abrogates NF‐κB p65-induced cell growth and resistance to sorafenib.
Fig. 6: The interaction between CYP1A2 and NF‐κB in SR cells.
Fig. 7: Expression of CYP1A2 and NF‐κB p65 in HCC patients and potential mechanism responsible for omeprazole to overcome the resistance to sorafenib in HCC treatment.

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Acknowledgements

We thank technical supports from Dr. Jianwei Ren, Mr. Rocky Lok-kee Ho and Ms. Suk-ying Chun. This study was supported by a grant from the Research Grants Council of the Hong Kong SAR, CUHK14117015.

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Authors and Affiliations

  1. Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China

    Jianqing Yu, Nuozhou Wang, Zhongqin Gong, George Gong Chen & Paul Bo San Lai

  2. Department of Hepatobiliary and Pancreas Surgery, the Second Clinical Medical College of Jinan University (Shenzhen People’s Hospital), Shenzhen, 524000, Guangdong, China

    Liping Liu

  3. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Shengli Yang

  4. Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, Prince of Walves Hospital, The Chinese University of Hong Kong, Hong Kong, China

    George Gong Chen

  5. Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China

    George Gong Chen

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Yu, J., Wang, N., Gong, Z. et al. Cytochrome P450 1A2 overcomes nuclear factor kappa B-mediated sorafenib resistance in hepatocellular carcinoma. Oncogene 40, 492–507 (2021). https://doi.org/10.1038/s41388-020-01545-z

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