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Vaccinia-related kinase 2 blunts sorafenib’s efficacy against hepatocellular carcinoma by disturbing the apoptosis-autophagy balance

Oncogene volume 40, pages 3378–3393 (2021)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Sorafenib is the only Food and Drug Administration (FDA)-approved first-line targeted drug for the treatment of advanced HCC. However, its effect on patient survival is limited. Recently, studies have demonstrated that the imbalance between apoptosis and autophagy plays a critical role in chemoresistance, and it is hypothesised that restoring the balance between these processes is a potential treatment strategy for improving chemoresistance in cancer. However, there is currently no evidence supporting this hypothesis. We aimed to investigate if vaccinia-related kinase 2 (VRK2), a serine/threonine protein kinase, confers sorafenib resistance in HCC cells. Here, we found that VRK2 was enriched in sorafenib-resistant HCC cells and patient-derived xenografts. Both in vivo and in vitro evidences showed that VRK2 blunts the efficacy of sorafenib against hepatocellular carcinoma by disturbing the balance between apoptosis and autophagy. Mechanistically, VRK2 promotes the phosphorylation of Bcl-2 by activating JNK1/MAPK8, thereby enhancing the dissociation of Bcl-2 from Beclin-1 and promoting the formation of the Beclin-1-Atg14-Vps34 complex, which facilitates autophagy. Furthermore, VRK2-induced phosphorylation of Bcl-2 promotes the interaction of Bcl-2 with BAX, thereby inhibiting apoptosis. In conclusion, targeting VRK2 for modulation of the balance between autophagy and apoptosis may be a novel strategy for overcoming sorafenib resistance in HCC.

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Fig. 1: VRK2 reduces the therapeutic effect of sorafenib in HCC in vitro and in vivo.
Fig. 2: VRK2 attenuates the sorafenib efficacy by regulating autophagy and apoptosis.
Fig. 3: VRK2 modulates Bcl-2/ Beclin-1 and Bcl-2/BAX complexes and affects the balance of autophagy and apoptosis in HCC.
Fig. 4: VRK2 regulating autophagy and apoptotic balance depends on Bcl-2 phosphorylation.
Fig. 5: VRK2 promotes Bcl-2 phosphorylation by activating JNK1/MAPK8 signalling pathway.
Fig. 6: IC261 therapy restores the balance of apoptosis and autophagy and improves the efficacy of sorafenib.
Fig. 7: Correlative expressions of VRK2, p-MAPK8 and LC3B are prognostic for clinical HCC.

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References

  1. Choo SP, Tan WL, Goh BKP, Tai WM, Zhu AX. Comparison of hepatocellular carcinoma in Eastern versus Western populations. Cancer 2016;122:3430–46.

    PubMed  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  PubMed  Google Scholar 

  3. Yang JD, Roberts LR. Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol. 2010;7:448–58.

    PubMed  PubMed Central  Google Scholar 

  4. Keating GM. Sorafenib: a review in hepatocellular carcinoma. Target Oncol. 2017;12:243–53.

    PubMed  Google Scholar 

  5. Li Y, Gao ZH, Qu XJ. The adverse effects of sorafenib in patients with advanced cancers. Basic Clin Pharm Toxicol. 2015;116:216–21.

    CAS  Google Scholar 

  6. Yang X, Pan X, Cheng X, Cheng Y, Kuang Y. Risk of treatment-related mortality with sorafenib in cancer patients: a meta-analysis of 20 randomly controlled trials: Risk of sorafenib-associated death. Int J Clin Pharm. 2015;37:1047–56.

    CAS  PubMed  Google Scholar 

  7. Wang K. Autophagy and apoptosis in liver injury. Cell Cycle. 2015;14:1631–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Sisinni L, Pietrafesa M, Lepore S, Maddalena F, Condelli V, Esposito F. et al. Endoplasmic reticulum stress and unfolded protein response in breast cancer: the balance between apoptosis and autophagy and its role in drug resistance. Int J Mol Sci. 2019;20:857–73.

    CAS  PubMed Central  Google Scholar 

  9. Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer. 2007;7:961–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017;17:528–42.

    CAS  PubMed  Google Scholar 

  11. Amaravadi R, Kimmelman AC, White E. Recent insights into the function of autophagy in cancer. Genes Dev. 2016;30:1913–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Perez-Hernandez M, Arias A, Martinez-Garcia D, Perez-Tomas R, Quesada R, Soto-Cerrato V. Targeting autophagy for cancer treatment and tumor chemosensitization. Cancers (Basel). 2019;11:1599–645.

    CAS  Google Scholar 

  13. Ho CJ, Gorski SM. Molecular mechanisms underlying autophagy-mediated treatment resistance in cancer. Cancers. 2019;11:1775–823.

    CAS  PubMed Central  Google Scholar 

  14. Ou J, Peng Y, Yang W, Zhang Y, Hao J, Li F, et al. ABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield. Nat Commun. 2019;10:1078.

    PubMed  PubMed Central  Google Scholar 

  15. Kfir-Erenfeld S, Sionov RV, Spokoini R, Cohen O, Yefenof E. Protein kinase networks regulating glucocorticoid-induced apoptosis of hematopoietic cancer cells: fundamental aspects and practical considerations. Leuk Lymphoma. 2010;51:1968–2005.

    CAS  PubMed  Google Scholar 

  16. Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 2015;524:309–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Nezu J, Oku A, Jones MH, Shimane M. Identification of two novel human putative serine/threonine kinases, VRK1 and VRK2, with structural similarity to vaccinia virus B1R kinase. Genomics 1997;45:327–31.

    CAS  PubMed  Google Scholar 

  18. Vega FM, Gonzalo P, Gaspar ML, Lazo PA. Expression of the VRK (vaccinia-related kinase) gene family of p53 regulators in murine hematopoietic development. FEBS Lett. 2003;544:176–80.

    CAS  PubMed  Google Scholar 

  19. Almarzooq S, Kwon J, Willis A, Craig J, Morris BJ. Novel alternatively-spliced exons of the VRK2 gene in mouse brain and microglial cells. Mol Biol Rep. 2020;47:5127–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Li M, Yue W. VRK2, a candidate gene for psychiatric and neurological disorders. Mol Neuropsychiatry. 2018;4:119–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Monsalve DM, Merced T, Fernandez IF, Blanco S, Vazquez-Cedeira M, Lazo PA. Human VRK2 modulates apoptosis by interaction with Bcl-xL and regulation of BAX gene expression. Cell Death Dis. 2013;4:e513.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Fernandez IF, Blanco S, Lozano J, Lazo PA. VRK2 inhibits mitogen-activated protein kinase signaling and inversely correlates with ErbB2 in human breast cancer. Mol Cell Biol. 2010;30:4687–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Vazquez-Cedeira M, Lazo PA. Human VRK2 (vaccinia-related kinase 2) modulates tumor cell invasion by hyperactivation of NFAT1 and expression of cyclooxygenase-2. J Biol Chem. 2012;287:42739–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Blanco S, Klimcakova L, Vega FM, Lazo PA. The subcellular localization of vaccinia-related kinase-2 (VRK2) isoforms determines their different effect on p53 stability in tumour cell lines. FEBS J. 2006;273:2487–504.

    CAS  PubMed  Google Scholar 

  25. Kim S, Lee D, Lee J, Song H, Kim HJ, Kim KT. Vaccinia-related kinase 2 controls the stability of the eukaryotic chaperonin TRiC/CCT by inhibiting the deubiquitinating enzyme USP25. Mol Cell Biol. 2015;35:1754–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu J, Liu W, Lu Y, Tian H, Duan C, Lu L, et al. Piperlongumine restores the balance of autophagy and apoptosis by increasing BCL2 phosphorylation in rotenone-induced Parkinson disease models. Autophagy 2018;14:845–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005;122:927–39.

    CAS  PubMed  Google Scholar 

  28. Maejima Y, Kyoi S, Zhai P, Liu T, Li H, Ivessa A, et al. Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat Med. 2013;19:1478–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ. 2011;18:571–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bassik MC, Scorrano L, Oakes SA, Pozzan T, Korsmeyer SJ. Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis. EMBO J. 2004;23:1207–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ito T, Deng X, Carr B, May WS. Bcl-2 phosphorylation required for anti-apoptosis function. J Biol Chem. 1997;272:11671–3.

    CAS  PubMed  Google Scholar 

  32. Vasilevskaya IA, Selvakumaran M, Roberts D, O’Dwyer PJ. JNK1 inhibition attenuates hypoxia-induced autophagy and sensitizes to chemotherapy. Mol Cancer Res. 2016;14:753–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156:477–91.e1.

    PubMed  Google Scholar 

  34. Goyal L, Zheng H, Abrams TA, Miksad R, Bullock AJ, Allen JN, et al. A phase II and biomarker study of sorafenib combined with modified FOLFOX in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2019;25:80–9.

    CAS  PubMed  Google Scholar 

  35. Cabral LKD, Tiribelli C, Sukowati CHC. Sorafenib resistance in hepatocellular carcinoma: the relevance of genetic heterogeneity. Cancers. 2020;12:1576–94.

    CAS  PubMed Central  Google Scholar 

  36. Mokdad AA, Hester CA, Singal AG, Yopp AC. Management of hepatocellular in the United States. Chin Clin Oncol. 2017;6:21.

    PubMed  Google Scholar 

  37. Meyer T, Fox R, Ma YT, Ross PJ, James MW, Sturgess R, et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2:565–75.

    PubMed  Google Scholar 

  38. Zhu YJ, Zheng B, Wang HY, Chen L. New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharm Sin. 2017;38:614–22.

    CAS  Google Scholar 

  39. Birendra K, May DG, Benson BV, Kim DI, Shivega WG, Ali MH, et al. VRK2A is an A-type lamin-dependent nuclear envelope kinase that phosphorylates BAF. Mol Biol Cell. 2017;28:2241–50.

    CAS  PubMed Central  Google Scholar 

  40. Zhao X, Liu J, Peng M, Liu J, Chen F. BMP4 is involved in the chemoresistance of myeloid leukemia cells through regulating autophagy-apoptosis balance. Cancer Invest. 2013;31:555–62.

    CAS  PubMed  Google Scholar 

  41. Kim R, Tanabe K, Uchida Y, Emi M, Inoue H, Toge T. Current status of the molecular mechanisms of anticancer drug-induced apoptosis. The contribution of molecular-level analysis to cancer chemotherapy. Cancer Chemother Pharm. 2002;50:343–52.

    CAS  Google Scholar 

  42. Tong M, Che N, Zhou L, Luk ST, Kau PW, Chai S, et al. Efficacy of annexin A3 blockade in sensitizing hepatocellular carcinoma to sorafenib and regorafenib. J Hepatol. 2018;69:826–39.

    CAS  PubMed  Google Scholar 

  43. Lu S, Yao Y, Xu G, Zhou C, Zhang Y, Sun J, et al. CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma. Cell Death Dis. 2018;9:646.

    PubMed  PubMed Central  Google Scholar 

  44. Gao L, Wang X, Tang Y, Huang S, Hu CA, Teng Y. FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. J Exp Clin Cancer Res. 2017;36:8.

    PubMed  PubMed Central  Google Scholar 

  45. Liu J, Liu W, Yang H. Balancing apoptosis and autophagy for Parkinson’s disease therapy: targeting BCL-2. ACS Chem Neurosci. 2019;10:792–802.

    PubMed  Google Scholar 

  46. Gordy C, He YW. The crosstalk between autophagy and apoptosis: where does this lead? Protein Cell. 2012;3:17–27.

    PubMed  PubMed Central  Google Scholar 

  47. Rubinstein AD, Kimchi A. Life in the balance - a mechanistic view of the crosstalk between autophagy and apoptosis. J Cell Sci. 2012;125:5259–68.

    CAS  PubMed  Google Scholar 

  48. Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell. 2008;30:678–88.

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by the National Natural Science Foundation of China (81760523).

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Author notes

  1. These authors contributed equally: Sisi Chen, Yunyan Du, Bin Xu

Authors and Affiliations

  1. Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China

    Sisi Chen & Leifeng Chen

  2. Department of Medical, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang, China

    Yunyan Du

  3. Department of Burns, First Affiliated Hospital of Nanchang University, Nanchang, China

    Bin Xu

  4. Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, China

    Qing Li

  5. Department of Pharmacy, Second Affiliated Hospital of Nanchang University, Nanchang, China

    Le Yang & Zi Jiang

  6. Department of Radiology, Second Affiliated Hospital of Nanchang University, Nanchang, China

    Zhaoxia Zeng

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Contributions

LC conceived, designed and supervised the execution of the entire project. SC, YD and BX initiated the project, designed experiments, and carried out major western blot, bioinformatic, cellular and animal studies. QL helped to establish IHC staining and pathological analyses. LY and ZJ were responsible for mass spectrometry analysis protein. ZZ analysed and interpreted the data. All authors have read and approved the final manuscript.

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Correspondence to Leifeng Chen.

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Chen, S., Du, Y., Xu, B. et al. Vaccinia-related kinase 2 blunts sorafenib’s efficacy against hepatocellular carcinoma by disturbing the apoptosis-autophagy balance. Oncogene 40, 3378–3393 (2021). https://doi.org/10.1038/s41388-021-01780-y

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