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 functions 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–fluorescein isothiocyanate/propidium iodide 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.
Highlights
With 841,000 newly diagnosed cases and 782,000 deaths annually, liver cancer ranked as the sixth most common cancer and the fourth leading cause for cancer-related deaths worldwide [1]
The differential effects of regorafenib in parental and regorafenib-resistant cells were confirmed by measurement of the expression levels of two apoptotic cascade-related proteins, B-cell leukemia/lymphoma 2 (Bcl2) and poly(ADP-ribose) polymerase (PARP)
Because S1P is the main product of sphingosine kinase 2 (SphK2), the present study revealed that S1P mediates regorafenib resistance in Hepatocellular carcinoma (HCC) cells
Summary
With 841,000 newly diagnosed cases and 782,000 deaths annually, liver cancer ranked as the sixth most common cancer and the fourth leading cause for cancer-related deaths worldwide [1]. Hepatocellular carcinoma (HCC), which accounts for 75 to 85% cases of primary liver cancer, is the most common pathological type of this deadly disease [2]. The majority of HCC patients are diagnosed at an advanced stage, which limited the applicability and efficacy of potentially curative therapies, including surgical resection and liver transplantation [3]. Approved by the US Food and Drug Administration in April 2017, regorafenib is currently used as a second-line systemic therapy for advanced HCC [4]. Despite the fact that regorafenib prolonged the survival of patients who had disease progression following sorafenib failure, the efficacy of this drug was still limited by primary or acquired therapy resistance [6]. Regorafenib is a second-line therapy drug used for advanced hepatocellular carcinoma (HCC). Sphingosine kinase 2 (SphK2) was targeted to reverse regorafenib resistance in HCC
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