Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Sorafenib-mediated cleavage of p62 initiates cellular senescence as a mechanism to evade its anti-hepatocellular carcinoma efficacy

Oncogene volume 43, pages 3003–3017 (2024)Cite this article

Subjects

Abstract

Hepatocellular carcinoma (HCC) stands as one of the most aggressively advancing and lethal malignancies. Sorafenib is presently endorsed as a primary therapy for advanced liver cancer, but its resistance presents a formidable challenge. Previous studies have implicated a connection between post-sorafenib discontinuation rebound and the development of drug resistance, yet the underlying mechanism remains elusive. In this study, we discerned that Sorafenib induced a senescent phenotype in HCC cells and caused a cleavage of ubiquitin-binding protein p62. Mechanistic studies establish that truncated p62 drives cellular senescence by promoting proteasome-dependent degradation of 4EBP1. Furthermore, truncated p62 induced specific ubiquitination of 4EBP1. Crucially, virtual drug screening uncovered that dacinostat inhibited cellular senescence by blocking sorafenib-induced p62 cleavage. In summary, our findings imply that truncated p62 from sorafenib cleavage promotes senescence via 4EBP1 degradation. The prevention of p62 cleavage could emerge as a crucial strategy for impeding the sorafenib-induced cellular senescence.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Sorafenib induces cellular senescence and cleavage of p62 in HCC.
Fig. 2: Sorafenib induced cellular senescence depends on the cleavage of p62.
Fig. 3: Truncated p62 initiates cellular senescence in HCC.
Fig. 4: Truncated p62 promotes proteasomal degradation of 4EBP1.
Fig. 5: Truncated p62 induces cellular senescence by downregulating 4EBP1.
Fig. 6: Truncated p62 binds to 4EBP1 and promotes ubiquitination of 4EBP1.
Fig. 7: Truncated p62 promotes the ubiquitination of 4EBP1 through Cullin 3 to induce cellular senescence in HCC.
Fig. 8: Dacinostat inhibits sorafenib-induced cellular senescence by blocking p62 cleavage.

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet (Lond, Engl). 2022;400:1345–62.

    Article  CAS  Google Scholar 

  2. Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015. JAMA Oncol. 2017;3:1683–91.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chan LK, Tsui YM, Ho DW, Ng IO. Cellular heterogeneity and plasticity in liver cancer. Semin cancer Biol. 2022;82:134–49.

    Article  CAS  PubMed  Google Scholar 

  4. Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: New trends. J Hepatol. 2020;72:250–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sia D, Villanueva A, Friedman SL, Llovet JM. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology. 2017;152:745–61.

    Article  CAS  PubMed  Google Scholar 

  6. Colagrande S, Inghilesi AL, Aburas S, Taliani GG, Nardi C, Marra F. Challenges of advanced hepatocellular carcinoma. World J Gastroenterol. 2016;22:7645–59.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Vogel A, Cervantes A, Chau I, Daniele B, Llovet JM, Meyer T, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol: Off J Eur Soc Med Oncol. 2018;29:iv238–iv55.

    Article  CAS  Google Scholar 

  8. Cheng K, Cai N, Zhu J, Yang X, Liang H, Zhang W. Tumor-associated macrophages in liver cancer: From mechanisms to therapy. Cancer Commun (Lond, Engl). 2022;42:1112–40.

    Article  Google Scholar 

  9. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatol (Baltim, Md). 2018;67:358–80.

    Article  Google Scholar 

  10. Rovesti G, Orsi G, Kalliopi A, Vivaldi C, Marisi G, Faloppi L, et al. Impact of Baseline Characteristics on the Overall Survival of HCC Patients Treated with Sorafenib: Ten Years of Experience. Gastrointest tumors. 2019;6:92–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gao R, Kalathur RKR, Coto-Llerena M, Ercan C, Buechel D, Shuang S, et al. YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. EMBO Mol Med. 2021;13:e14351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Qin S, Chan SL, Gu S, Bai Y, Ren Z, Lin X, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet (Lond, Engl). 2023;402:1133–46.

    Article  CAS  Google Scholar 

  13. Morse MA, Sun W, Kim R, He AR, Abada PB, Mynderse M, et al. The Role of Angiogenesis in Hepatocellular Carcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res. 2019;25:912–20.

    Article  CAS  Google Scholar 

  14. Leung CON, Tong M, Chung KPS, Zhou L, Che N, Tang KH, et al. Overriding Adaptive Resistance to Sorafenib Through Combination Therapy With Src Homology 2 Domain-Containing Phosphatase 2 Blockade in Hepatocellular Carcinoma. Hepatol (Baltim, Md). 2020;72:155–68.

    Article  CAS  Google Scholar 

  15. Xu J, Ji L, Liang Y, Wan Z, Zheng W, Song X, et al. CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1. Signal Transduct Target Ther. 2020;5:298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wei L, Lee D, Law CT, Zhang MS, Shen J, Chin DW, et al. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nat Commun. 2019;10:4681.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer. Nat Rev Cancer. 2022;22:340–55.

    Article  CAS  PubMed  Google Scholar 

  18. Wang C, Vegna S, Jin H, Benedict B, Lieftink C, Ramirez C, et al. Inducing and exploiting vulnerabilities for the treatment of liver cancer. Nature. 2019;574:268–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sweet KL, Hazlehurst LA, Pinilla-Ibarz J. The one-two punch: combination treatment in chronic myeloid leukemia. Crit Rev Oncol/Hematol. 2013;88:667–79.

    Article  PubMed  Google Scholar 

  20. Ren G, Kang Y. A one-two punch of miR-126/126* against metastasis. Nat cell Biol. 2013;15:231–3.

    Article  CAS  PubMed  Google Scholar 

  21. Sánchez-Martín P, Saito T, Komatsu M. p62/SQSTM1: ‘Jack of all trades’ in health and cancer. FEBS J. 2019;286:8–23.

    Article  PubMed  Google Scholar 

  22. Umemura A, He F, Taniguchi K, Nakagawa H, Yamachika S, Font-Burgada J, et al. p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells. Cancer cell. 2016;29:935–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tan CT, Soh NJH, Chang HC, Yu VC. p62/SQSTM1 in liver diseases: the usual suspect with multifarious identities. FEBS J. 2023;290:892–912.

    Article  CAS  PubMed  Google Scholar 

  24. Tao M, Liu T, You Q, Jiang Z. p62 as a therapeutic target for tumor. Eur J medicinal Chem. 2020;193:112231.

    Article  CAS  Google Scholar 

  25. Islam MA, Sooro MA, Zhang P. Autophagic Regulation of p62 is Critical for Cancer Therapy. Int J Mol Sci. 2018;19:1405.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhao Y, Zhu Q, Bu X, Zhou Y, Bai D, Guo Q, et al. Triggering apoptosis by oroxylin A through caspase-8 activation and p62/SQSTM1 proteolysis. Redox Biol. 2020;29:101392.

    Article  CAS  PubMed  Google Scholar 

  27. Agard NJ, Maltby D, Wells JA. Inflammatory stimuli regulate caspase substrate profiles. Mol Cell Proteom : MCP. 2010;9:880–93.

    Article  CAS  PubMed  Google Scholar 

  28. Sanchez-Garrido J, Sancho-Shimizu V, Shenoy AR. Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing. Sci Signal. 2018;11:eaat6903.

    Article  CAS  PubMed  Google Scholar 

  29. Llanos S, García-Pedrero JM, Morgado-Palacin L, Rodrigo JP, Serrano M. Stabilization of p21 by mTORC1/4E-BP1 predicts clinical outcome of head and neck cancers. Nat Commun. 2016;7:10438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yanagiya A, Suyama E, Adachi H, Svitkin YV, Aza-Blanc P, Imataka H, et al. Translational homeostasis via the mRNA cap-binding protein, eIF4E. Mol cell. 2012;46:847–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xia S, Pan Y, Liang Y, Xu J, Cai X. The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. EBioMedicine. 2020;51:102610.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020;5:87.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Huang A, Yang XR, Chung WY, Dennison AR, Zhou J. Targeted therapy for hepatocellular carcinoma. Signal Transduct Target Ther. 2020;5:146.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Qiu WL, Tseng AJ, Hsu HY, Hsu WH, Lin ZH, Hua WJ, et al. Fucoidan increased the sensitivity to gefitinib in lung cancer cells correlates with reduction of TGFβ-mediated Slug expression. Int J Biol macromolecules. 2020;153:796–805.

    Article  CAS  Google Scholar 

  35. Zhao D, Zhai B, He C, Tan G, Jiang X, Pan S, et al. Upregulation of HIF-2α induced by sorafenib contributes to the resistance by activating the TGF-α/EGFR pathway in hepatocellular carcinoma cells. Cell Signal. 2014;26:1030–9.

    Article  CAS  PubMed  Google Scholar 

  36. Atadja P, Gao L, Kwon P, Trogani N, Walker H, Hsu M, et al. Selective growth inhibition of tumor cells by a novel histone deacetylase inhibitor, NVP-LAQ824. Cancer Res. 2004;64:689–95.

    Article  CAS  PubMed  Google Scholar 

  37. Zhao J, Bai D, Qi L, Cao W, Du J, Gu C, et al. The flavonoid GL-V9 alleviates liver fibrosis by triggering senescence by regulating the transcription factor GATA4 in activated hepatic stellate cells. Br J Pharmacol. 2023;180:1072–89.

    Article  CAS  PubMed  Google Scholar 

  38. Bai D, Zhao J, Wang R, Du J, Zhou C, Gu C, et al. Eubacterium coprostanoligenes alleviates chemotherapy-induced intestinal mucositis by enhancing intestinal mucus barrier. Acta Pharm Sin B. 2024;14:1677–92.

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82373910, 82204409). The “Double First-Class” University Project (CPU2022QZ20). We thank Mrs. Liuyi Zhong from Pharmaceutical Animal Experimental Center in China Pharmaceutical University for her kind help in the in vivo experiments.

Author information

Author notes

  1. These authors contributed equally: Jiaying Du, Dongsheng Bai.

Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People’s Republic of China

    Jiaying Du, Dongsheng Bai, Chunyang Gu, Jiawei Zhao, Chen Zhou, Yuxiang Wang, Yue Zhao & Na Lu

Authors
  1. Jiaying Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dongsheng Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chunyang Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiawei Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chen Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuxiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yue Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Na Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JD designed experiments and wrote the manuscript, DB analyzed experiments data; CG performed cell studies, JZ performed animal studies; YW and CZ edited the manuscript; YZ and NL directed this project and supervised the overall project. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Yue Zhao or Na Lu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate statement

All mice received human care and animal experiments were approved by the University Committee on Use and Care of Animals of the China Pharmaceutical University (Nanjing, China) (Approval No.2020-0701). All experimental protocols followed ARRIVE guidelines. All participants consented to publish the paper.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Du, J., Bai, D., Gu, C. et al. Sorafenib-mediated cleavage of p62 initiates cellular senescence as a mechanism to evade its anti-hepatocellular carcinoma efficacy. Oncogene 43, 3003–3017 (2024). https://doi.org/10.1038/s41388-024-03142-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-024-03142-w

Search

Advanced search

Quick links