FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model
Journal of Translational Medicine
Methods: Cell 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 antitumor eﬃcacy and toxicity proﬁle of FTY720 in vivo.
Results: We 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.
Conclusions: Our preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment.
Agata Szymiczek, Sandra Pastorino, David Larson, Mika Tanji, Laura Pellegrini, Jiaming Xue, Shuangjing Li, Carlotta Giorgi, Paolo Pinton, Yasutaka Takinishi, Harvey I. Pass, Hideki Furuya, Giovanni Gaudino, Andrea Napolitano, Michele Carbone and Haining Yang