FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model

Abstract

BackgroundMalignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet.MethodsCell viability and anchorage–independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy. The mechanism of action of FTY720 in MM was assessed by measuring the activity of phosphatase protein 2A (PP2A)—a major target of FTY720. The binding of the endogenous inhibitor SET to PP2A in presence of FTY720 was evaluated by immunoblotting and immunoprecipitation. Signaling and activation of programmed cell death were evaluated by immunoblotting and flow cytometry. A syngeneic mouse model was used to evaluate anti-tumor efficacy and toxicity profile of FTY720 in vivo.ResultsWe show that FTY720 significantly suppressed MM cell viability and anchorage–independent growth without affecting normal HM cells. FTY720 inhibited the phosphatase activity of PP2A by displacement of SET protein, which appeared overexpressed in MM, as compared to HM cells. FTY720 promoted AKT dephosphorylation and Bcl-2 degradation, leading to induction of programmed cell death, as demonstrated by caspase-3 and PARP activation, as well as by cytochrome c and AIF intracellular translocation. Moreover, FTY720 administration in vivo effectively reduced tumor burden in mice without apparent toxicity.ConclusionsOur preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1158-z) contains supplementary material, which is available to authorized users.

Investigation of PP2A and Its Endogenous Inhibitors in Neuroblastoma Cell Survival and Tumor Growth

“…Previous investigations have postulated that the effects of FTY720-induced PP2A activation may be dependent upon dephosphorylation of AKT. Loss of AKT phosphorylation has been noted in breast and prostate cancer cells and mesothelioma [17] , [20] , [23] . In this study, FTY720 treatment resulted in an increase in AKT phosphorylation in all four neuroblastoma cell lines tested.…”

“…Once tumors were palpable (100 mm 3 ), the mice were randomized to receive either 50 μl suspension vehicle (ORA-Plus, Perrigo, Allegan, MI) or FTY720 10 mg/kg/day suspended in 50 μl ORA-Plus once daily via oral gavage. The FTY720 dosing was based on previous animal studies [16] , [17] , [18] . The flank tumors were measured twice weekly using calipers, and tumor volumes were calculated.…”

A genome-wide screen for FTY720-sensitive mutants reveals genes required for ROS homeostasis

“…Notably, FTY720 has been reported to exert antitumor properties against breast cancers 3 4 5 , glioblastoma 6 7 8 , hepatocellular carcinoma 9 10 11 , and malignant mesothelioma 12 , implying that FTY720 action is involved in multiple intracellular signaling pathways related to cancer signaling. Intriguingly, FTY720 exerts its anticancer property largely independent of the phosphorylation of the drug, suggesting that activation of S1P receptor is not relevant for cell death 4 8 11 12 13 14 . Various signaling molecules such as protein phosphatase 2A, JNK, Akt, and Sphk have been found to mediate anticancer effects associated with FTY720 4 8 12 15 .…”

“…Intriguingly, FTY720 exerts its anticancer property largely independent of the phosphorylation of the drug, suggesting that activation of S1P receptor is not relevant for cell death 4 8 11 12 13 14 . Various signaling molecules such as protein phosphatase 2A, JNK, Akt, and Sphk have been found to mediate anticancer effects associated with FTY720 4 8 12 15 . In particular, the importance of the FTY720-mediated ROS generation in inducing apoptosis in various cancer cell types has been highlighted in several reports 8 10 11 14 15 16 .…”

Chemical genetic analysis of FTY720‐ and Ca2+‐sensitive mutants reveals a functional connection between FTY720 and membrane trafficking

“…effects, mostly independently of S1P receptors (Omar et al, 2011, Szymiczek et al, 2017, Payne et al, 2007. Thus, in addition to its immunomodulatory role, FTY720 has the potential for treating cancer and inflammatory diseases.…”