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

Journal of Translational Medicine

Research

Harvey I. Pass¹  Carlotta Giorgi²  Paolo Pinton²  Laura Pellegrini³  Sandra Pastorino³  Hideki Furuya³  Agata Szymiczek³  David Larson³  Giovanni Gaudino³  Yasutaka Takinishi³  Andrea Napolitano³  Shuangjing Li³  Mika Tanji³  Haining Yang³  Michele Carbone³  Jiaming Xue³ 

[1] Department of Cardiothoracic Surgery, New York University Langone Medical Center, 10065, New York, NY, USA;Department of Morphology-Surgery-Experimental Medicine, University of Ferrara, Ferrara, Italy;Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, 96813, Honolulu, HI, USA;

关键词: Malignant mesothelioma;    Therapeutic;    Drug repurposing;    FTY720;    PP2A;    Apoptosis;   

DOI  :  10.1186/s12967-017-1158-z

 received in 2017-01-17, accepted in 2017-03-06,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2017