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01.12.2017 | Research | Ausgabe 1/2017 Open Access

Journal of Translational Medicine 1/2017

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

Zeitschrift:
Journal of Translational Medicine > Ausgabe 1/2017
Autoren:
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, Haining Yang
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12967-017-1158-z) contains supplementary material, which is available to authorized users.

Abstract

Background

Malignant 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.

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 anti-tumor 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.
Zusatzmaterial
Additional file 1: Figure S1. FTY720 does not affect MM cell migration.
Additional file 2: Figure S2. FTY720-P does not affect MM cell survival.
Additional file 3: Figure S3. FTY720 does not alter SET and CIP2A protein expression levels in MM cells.
Additional file 4: Figure S4. FTY720 inhibits SphK1.
Additional file 5: Figure S5. FTY720 induces apoptosis in MM cells.
Additional file 6: Figure S6. FTY720 displaces PP2A inhibitor protein –SET, reduces pAKT and Bcl2, and activates apoptosis in AB1 mouse cells.
Literatur
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