PTEN- and p53-mediated apoptosis and cell cycle arrest by FTY720 in gastric cancer cells and nude mice.
FTY720, a new immunosuppressant, derived from ISP-1, has been studied for its putative anti-cancer properties in the recent years. In this study, we have reported that FTY720 greatly inhibited gastric cancer cell proliferation for the first time, and found this effect was associated with G1 phase cell cycle arrest and apoptosis. Results from our Western blotting and Real-time PCR showed that FTY720 induced obvious PTEN expression in a p53-independent way, consistent with a substantial decrease in p-Akt and MDM2. FTY720 dramatically increased the expression of Cip1/p21, p27, and BH3-only proteins through the accumulation of p53 by PTEN-mediated inhibition of the PI3K/Akt/MDM2 signaling. Suppression of PTEN expression with siRNA significantly reduced the p53 and p21 levels and activated Akt, resulting in decreased apoptosis and increased cell survival. Furthermore, we have observed an additive effect of FTY720 in killing gastric cancer cells when in combination with Cisplatin, partly through PTEN-mediated Akt/MDM2 inhibition. In vivo study has also shown that tumor growth was significantly suppressed after FTY720 treatment. In conclusion, our results suggest that FTY720 induces a significant increase of PTEN, which inhibits p-Akt and MDM2, and then increases the level of p53, thereby inducing G1 phase arrest and apoptosis. We have characterized a novel immunosuppressant, for the first time, which shows potential anti-tumor effects on gastric cancer by PTEN activation through p53-independent mechanism, especially in combination with Cisplatin. This PTEN target-based therapy is worth further investigation and warrants clinical evaluation.
Zheng
Tongsen
T
Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China. zhengtongsen@hotmail.com
Meng
Xianzhi
X
Wang
Jiabei
J
Chen
Xi
X
Yin
Dalong
D
Liang
Yingjian
Y
Song
Xuan
X
Pan
Shangha
S
Jiang
Hongchi
H
Liu
Lianxin
L
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D000068876:Fingolimod Hydrochloride; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D002945:Cisplatin