CoChat
Sign Up
Cited by 61Sphingolipid Metabolism and SignalingHepatocellular Carcinoma Treatment and PrognosisCancer, Lipids, and Metabolism

Targeting SphK2 reverses acquired resistance of Regorafenib in hepatocellular carcinoma

Open access
Shi, Weiwei, Zhang, Shan, Ma, Ding, Yan, Dongliang, Zhang, Guang, Cao, Yin, Wang, Zhongxia, Wu, Junhua +1 more·2020·Frontiers in Oncology
DOI 10.3389/fonc.2020.00694PMC PMC7327090
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: Regorafenib is a second-line therapy drug used for advanced hepatocellular carcinoma (HCC). Unfortunately, the survival benefit of the patients receiving this treatment is modest, which may be attributed to drug resistance. In the present study, Sphingosine kinase 2 (SphK2) was targeted to reverse regorafenib-resistance in HCC. Methods: The function of SphK2 and sphingosine-1-phosphate (S1P), the catalytic product of SphK2 in regorafenib-resistance of HCC cells were evaluated by cell counting kit-8 assay, colony formation, cell cycle evaluation and Annexin V-FITC/PI double staining assay. The antitumor activity of combined treatment of regorafenib and the SphK2 specific inhibitor ABC294640 was examined in HCC cells in vitro and xenograft model in vivo. The molecular mechanisms of SphK2/S1P mediating regorafenib-resistance were investigated using cell line establishment and western blot analysis. Results: Well developed regorafenib-resistant HCC cells indicated high expression levels of SphK2. The sensitivity to regorafenib of regorafenib-resistant HCC cells was restored following SphK2 knockdown or pharmacological inhibition by ABC294640. In addition, ectopic expression of SphK2 and exogenous addition of S1P decreased the sensitivity of HCC cells to regorafenib. Furthermore, the combination treatment with ABC294640 sensitized resistant tumor to regorafenib in xenograft model of HCC. The phosphorylation levels of nuclear factor κB (NF-κB) as well as those of signal transducer and activator of transcription 3 (STAT3) were positively associated with SphK2 and S1P. Conclusions: SphK2/S1P mediates regorafenib resistance of HCC through NF-κB and STAT3 activation. Targeting SphK2 by ABC294640 potently reduces regorafenib resistance of HCC cells both in vitro and in vivo. The combination of ABC294640 and regorafenib could be developed as a novel potential treatment strategy for advanced HCC.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fonc.2020.00694

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • SphK2 expression and nuclear translocation of p65 were increased in regorafenib-resistant hepatocellular carcinoma-derived cells.

    “SphK2 expression and nuclear translocation of p65 were increased in these cells.”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [55]

    The Results section on SphK2 expression reports that SphK2 was significantly upregulated in regorafenib-resistant HCC cells compared with parental cells. The Results section on NF-κB and STAT3 reports increased phosphorylation of p65, but does not report increased nuclear translocation of p65. Phosphorylation does not establish the claimed change in cellular location. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Increased SphK2 expression activates the NF-κB pathway.

    “activation of the NF-κB pathway by increased SphK2 expression was similar to that observed in regorafenib-resistant hepatocellular carcinoma-derived cells (55)”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [55]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 42

  1. [1]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. 10.3322/caac.21492 30207593 · DOI · Paper page
  2. [2]Ayuso C Rimola J Vilana R Burrel M Darnell A Garcia-Criado A. Diagnosis and staging of hepatocellular carcinoma (HCC): current guidelines. Eur J Radiol. (2018) 101: 72– 81. 10.1016/j.ejrad.2018.01.025 29571804 · DOI
  3. [3]Kim DW Talati C Kim R. Hepatocellular carcinoma (HCC): beyond sorafenib-chemotherapy. J Gastrointest Oncol. (2017) 8: 256– 65. 10.21037/jgo.2016.09.07 28480065 PMC5401857 · DOI
  4. [4]Rimassa L Pressiani T Merle P. Systemic treatment options in hepatocellular carcinoma. Liver Cancer. (2019) 8: 427– 46. 10.1159/000499765 31799201 PMC6883446 · DOI
  5. [5]Mirone G Perna S Shukla A Marfe G. Involvement of notch-1 in resistance to regorafenib in colon cancer cells. J Cell Physiol. (2016) 231: 1097– 105. 10.1002/jcp.25206 26419617 · DOI
  6. [6]Bruix J Qin S Merle P Granito A Huang YH Bodoky G. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. (2017) 389: 56– 66. 10.1016/S0140-6736(16)32453-9 27932229 · DOI
  7. [7]Tutusaus A Stefanovic M Boix L Cucarull B Zamora A Blasco L. Antiapoptotic BCL-2 proteins determine sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma. Oncotarget. (2018) 9: 16701– 17. 10.18632/oncotarget.24673 29682179 PMC5908280 · DOI
  8. [8]Xie Z Liu H Geng M. Targeting sphingosine-1-phosphate signaling for cancer therapy. Sci China Life Sci. (2017) 60: 585– 600. 10.1007/s11427-017-9046-6 28623546 · DOI
  9. [9]Plano D Amin S Sharma AK. Importance of sphingosine kinase (SphK) as a target in developing cancer therapeutics and recent developments in the synthesis of novel SphK inhibitors. J Med Chem. (2014) 57: 5509– 24. 10.1021/jm4011687 24471412 · DOI
  10. [10]Wang F Wu Z. Sphingosine kinase 1 overexpression is associated with poor prognosis and oxaliplatin resistance in hepatocellular carcinoma. Exp Ther Med. (2018) 15: 5371– 6. 10.3892/etm.2018.6086 29844803 PMC5958821 · DOI
  11. [11]Hasanifard L Sheervalilou R Majidinia M. New insights into the roles and regulation of SphK2 as a therapeutic target in cancer chemoresistance. J Cell Physiol. (2019) 234: 8162– 81. 10.1002/jcp.27612 30456838 · DOI
  12. [12]Liu J Zhou Q Wu CP Xu YW Liu WL Zhao HF. SPHK2 protein expression, Ki-67 index and infiltration of tumor-associated macrophages (TAMs) in human glioma. Histol Histopathol. (2018) 33: 987– 94. 10.14670/HH-11-995 29697136 · DOI
  13. [13]Liu W Ning J Li C Hu J Meng Q Lu H. Overexpression of Sphk2 is associated with gefitinib resistance in non-small cell lung cancer. Tumour Biol. (2016) 37: 6331– 6. 10.1007/s13277-015-4480-1 26628299 · DOI
  14. [14]Sun E Zhang W Wang L Wang A Ma C Lei M. Down-regulation of Sphk2 suppresses bladder cancer progression. Tumour Biol. (2016) 37: 473– 8. 10.1007/s13277-015-3818-z 26224479 · DOI
  15. [15]Dai L Smith CD Foroozesh M Miele L Qin Z. The sphingosine kinase 2 inhibitor ABC294640 displays anti-non-small cell lung cancer activities in vitro and in vivo. Int J Cancer. (2018) 142: 2153– 62. 10.1002/ijc.31234 29277894 PMC5867242 · DOI
  16. [16]Shi WN Cui SX Song ZY Wang SQ Sun SY Yu XF. Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXRalpha by K48/K63-linked polyubiquitination. Oncotarget. (2017) 8: 39605– 17. 10.18632/oncotarget.17174 28465486 PMC5503636 · DOI · Paper page
  17. [17]Antoon JW White MD Meacham WD Slaughter EM Muir SE Elliott S. Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640. Endocrinology. (2010) 151: 5124– 35. 10.1210/en.2010-0420 20861237 PMC2954724 · DOI
  18. [18]Venant H Rahmaniyan M Jones EE Lu P Lilly MB Garrett-Mayer E. The sphingosine kinase 2 inhibitor ABC294640 reduces the growth of prostate cancer cells and results in accumulation of dihydroceramides in vitro and in vivo. Mol Cancer Ther. (2015) 14: 2744– 52. 10.1158/1535-7163.MCT-15-0279 26494858 PMC4674301 · DOI
  19. [19]Beljanski V Lewis CS Smith CD. Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts. Cancer Biol Ther. (2011) 11: 524– 34. 10.4161/cbt.11.5.14677 21258214 PMC3087901 · DOI
  20. [20]Yang J Yang C Zhang S Mei Z Shi M Sun S. ABC294640, a sphingosine kinase 2 inhibitor, enhances the antitumor effects of TRAIL in non-small cell lung cancer. Cancer Biol Ther. (2015) 16: 1194– 204. 10.1080/15384047.2015.1056944 26054751 PMC4623419 · DOI
  21. [21]Beljanski V Knaak C Zhuang Y Smith CD. Combined anticancer effects of sphingosine kinase inhibitors and sorafenib. Invest New Drugs. (2011) 29: 1132– 42. 10.1007/s10637-010-9452-0 20473784 PMC3089696 · DOI
  22. [22]Tang ZY Sun FX Tian J Ye SL Liu YK Liu KD Metastatic human hepatocellular carcinoma models in nude mice and cell line with metastatic potential. World J Gastroenterol. (2001) 7: 597– 601. 10.3748/wjg.7.597 11819839 PMC4695559 · DOI
  23. [23]Tian J Tang ZY Ye SL Liu YK Lin ZY Chen J. New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis. Br J Cancer. (1999) 81: 814– 21. 10.1038/sj.bjc.6690769 10555751 PMC2374300 · DOI
  24. [24]Tobita K Ohori K. Polypeptide analysis of hepatitis-virus type-B surface-antigen 559 produced by a human hepatoma-cell line, PLC-PRF-5. Acta Virol. (1980) 24: 367- &. 6108067
  25. [25]Jung CW Song T-J Lee K-O Choi SB Kim WB Suh SO. Characterization of hepatocellular carcinoma cell lines based on cell adhesion molecules. Int J Mol Med. (2012) 29: 1158– 64. 10.3892/ijmm.2012.951 22447134 · DOI
  26. [26]Wang F He L Dai W-Q Xu Y-P Wu D Lin C-L. Salinomycin inhibits proliferation and induces apoptosis of human hepatocellular carcinoma cells in vitro and in vivo. PLoS ONE. (2012) 7: 638. 10.1371/journal.pone.0050638 23284640 PMC3527475 · DOI
  27. [28]Sherman M. Regorafenib for treatment of hepatocellular carcinoma. Hepatology. (2018) 67: 1162– 5. 10.1002/hep.29598 29059458 · DOI
  28. [29]Guillermet-Guibert J Davenne L Pchejetski D Saint-Laurent N Brizuela L Guilbeau-Frugier C. Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug. Mol Cancer Ther. (2009) 8: 809– 20. 10.1158/1535-7163.MCT-08-1096 19372554 · DOI
  29. [30]Ponnusamy S Meyers-Needham M Senkal CE Saddoughi SA Sentelle D Selvam SP. Sphingolipids and cancer: ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance. Fut Oncol. (2010) 6: 1603– 24. 10.2217/fon.10.116 21062159 PMC3071292 · DOI
  30. [31]Baran Y Salas A Senkal CE Gunduz U Bielawski J Obeid LM. Alterations of ceramide/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukemia cells. J Biol Chem. (2007) 282: 10922– 34. 10.1074/jbc.M610157200 17303574 · DOI
  31. [32]Antoon JW White MD Slaughter EM Driver JL Khalili HS Elliott S Targeting NF kappa B mediated breast cancer chemoresistance through selective inhibition of sphingosine kinase-2. Cancer Biol Ther. (2011) 11: 678– 89. 10.4161/cbt.11.7.14903 21307639 PMC3084971 · DOI
  32. [33]Akao Y Banno Y Nakagawa Y Hasegawa N Kim TJ Murate T. High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation. Biochem Biophys Res Commun. (2006) 342: 1284– 90. 10.1016/j.bbrc.2006.02.070 16516161 · DOI
  33. [34]Zhang L Wang X Bullock AJ Callea M Shah H Song J. Anti-S1P Antibody as a novel therapeutic strategy for VEGFR TKI-resistant renal cancer. Clin Cancer Res. (2015) 21: 1925– 34. 10.1158/1078-0432.CCR-14-2031 25589614 PMC4419371 · DOI
  34. [35]Cheng JC Wang EY Yi Y Thakur A Tsai SH Hoodless PA. S1P Stimulates proliferation by upregulating CTGF expression through S1PR2-mediated YAP activation. Mol Cancer Res. (2018) 16: 1543– 55. 10.1158/1541-7786.MCR-17-0681 29903770 · DOI
  35. [36]Taniguchi M Kitatani K Kondo T Hashimoto-Nishimura M Asano S Hayashi A. Regulation of autophagy and its associated cell death by “sphingolipid rheostat”: reciprocal role of ceramide and sphingosine 1-phosphate in the mammalian target of rapamycin pathway. J Biol Chem. (2012) 287: 39898– 910. 10.1074/jbc.M112.416552 23035115 PMC3501064 · DOI · Paper page
  36. [37]White MD Chan L Antoon JW Beckman BS. Targeting ovarian cancer and chemoresistance through selective inhibition of sphingosine kinase-2 with ABC294640. Anticancer Res. (2013) 33: 3573– 9. 24023282
  37. [38]Meiyanto E Putri DD Susidarti RA Murwanti R Sardjiman Fitriasari A. Curcumin and its analogues (PGV-0 and PGV-1) enhance sensitivity of resistant MCF-7 cells to doxorubicin through inhibition of HER2 and NF-kB activation. Asian Pac J Cancer Prev. (2014) 15: 179– 84. 10.7314/APJCP.2014.15.1.179 24528023 · DOI
  38. [39]Tai WT Cheng AL Shiau CW Liu CY Ko CH Lin MW. Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3. Mol Cancer Ther. (2012) 11: 452– 63. 10.1158/1535-7163.MCT-11-0412 22180308 · DOI
  39. [40]Shi L Wang S Zangari M Xu H Cao TM Xu C. Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance. Oncotarget. (2010) 1: 22– 33. 10.18632/oncotarget.105 20930946 PMC2949973 · DOI
  40. [41]Deshpande GP Imamdin A Lecour S Opie LH. Sphingosine-1-phosphate (S1P) activates STAT3 to protect against de novo acute heart failure (AHF). Life Sci. (2018) 196: 127– 32. 10.1016/j.lfs.2018.01.023 29373815 · DOI
  41. [42]He C Dong X Zhai B Jiang X Dong D Li B. MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway. Oncotarget. (2015) 6: 28867– 81. 10.18632/oncotarget.4814 26311740 PMC4745697 · DOI
  42. [43]French KJ Zhuang Y Maines LW Gao P Wang W Beljanski V. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther. (2010) 333: 129– 39. 10.1124/jpet.109.163444 20061445 PMC2846016 · DOI

Cited by

Sorted by citations

Authors
Shi, W., Zhang, S., Ma, D., Yan, D., Zhang, G., Cao, Y., Wang, Z., Wu, J., & Jiang, C.
Affiliations
  • Nanjing Drum Tower Hospital (CN)
  • Nanjing University (CN)
Corresponding author
  • Wang, Zhongxia
  • Wu, Junhua
  • Jiang, Chunping
ORCID
Venue
Frontiers in Oncology
Publisher
Frontiers Media SA
Published
2020-06-24
Volume
10
Pages
694-694
ISSN
2234-943X (ISSN-L)
DOI
10.3389/fonc.2020.00694
PMC
PMC7327090
OpenAlex
W3037255929
Cited by
61
References
1
Citations by year
2026: 4 · 2025: 9 · 2024: 13 · 2023: 20 · 2022: 11 · 2021: 3 · 2020: 1
FWCI
2.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81572393, 81602093, 81972888)
  • Natural Science Foundation of Jiangsu Province (BK20141324, BK20160118)
  • Medical Science and Technology Development Foundation, Nanjing Municipality Health Bureau (ZKX15020, ZKX17022)
  • Fundamental Research Funds for the Central Universities (021414380215, 021414380242, 021414380258, 14380329/3)
  • Jiangsu Provincial Key Research and Development Program (BE2018701)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
sphingosine kinase 2, sphingosine-1-phosphate, regorafenib resistance, hepatocellular carcinoma, ABC294640, NF-κB, STAT3, combination therapy, drug resistance reversal

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review