A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells

Abstract

1 Our previous studies revealed that the immunosuppressive agent, FTY720, mainly induces mitochondria-involved apoptosis in some types of cancer cells, since Bcl-2 overexpression prevents the FTY720-induction of apoptotic stimuli. Furthermore, FTY720 induces G0/G1 cell cycle arrest. The present study further examines the correlation between intracellular signaling kinases with FTY720-induced mitochondria-involved apoptosis. 2 Human T cell leukemia Jurkat was exposed to FTY720. Dephosphorylation of Akt occurred in a time-and concentration-dependent manner. FTY720 also induced Bad (Ser 136 ) and ribosomal p70S6 kinase (p70 S6k ) (Thr 389 ) dephosphorylation. 3 FTY720-induced Akt dephosphorylation was not because of Akt upstream phosphatidylinositol 3 0 -kinase (PI 3-kinase) pathway inhibition. 4 FTY720 also induced Akt dephosphorylation in human B cell leukemia BALL-1. BALL-1 cells were resistant to FTY720-induced apoptosis. 5 Okadaic acid (OA) inhibited the FTY720-induced dephosphorylation of Akt and p70 S6k , suggesting that FTY720 promotes Ser/Thr protein phosphatase (PP) activity. 6 OA partially inhibited FTY720-induced caspase-3 activation. 7 PP2A or PP2A-like phosphatase was temporarily activated in cells exposed to FTY720. In addition, FTY720 activated purified PP2A (ABC). 8 Overall, the results suggest that FTY720 activated PP2A or PP2A-like phosphatase and dephosphorylated Akt pathway factors resulting in the enhancement of apoptosis via mitochondria. British Journal of Pharmacology (2003) 138, 1303 -1312. doi:10.1038/sj.bjp.0705182 Keywords: FTY720; Akt; PKB; P70 S6k ; Bad; PP2A; apoptosis; leukemia cells Abbreviations: CDK, cyclin-dependent kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; OA, okadaic acid; p70 S6k , ribosomal p70 S6 kinase; PDGF, platelet-derived growth factor; PDK, phosphoinositide-dependent kinase; PDK1, phosphoinositide-dependent kinase 1; phospho-, phosphorylated; PI(3,4)P 2 , phosphatidylinositol 3,4-diphosphate; PI(3,4,5)P 3 , phosphatidylinositol 3,4,5-triphosphate; PI 3-kinase, phosphatidylinositol 3 0 -kinase; PI(4,5)P 2 , phosphatidylinositol 4,5-diphosphate; PP, protein phosphatase; pRb, retinoblastoma protein; SGK, serum and glucocorticoid-inducible kinase; DC m , mitochondrial membrane potential

FTY720 induces necrotic cell death and autophagy in ovarian cancer cells: A protective role of autophagy

“…There is now a growing body of evidence showing a powerful therapeutic potential of FTY720 in treatment of various types of cancers, [9][10][11][12][13][14][15]18,29,30 although the underlying mechanisms remain to be clarified. The findings described herein demonstrate for the first time that FTY720 is a potent toxic agent towards ovarian cancer cells.…”

“…The antitumor activity of FTY720 has been documented in several cancer models, [9][10][11][12][13][14][15] but not yet in ovarian cancer. We (c) OV2008 and iGROV-1 cells were treated for 24 hrs with 5 μM FTY720 or 5 μM cDDP, and then clonogenic survival assay was conducted as described in Methods.…”

“…In addition to the immunosuppressive effects, FTY720 has also shown preclinical antitumor efficacy in various cancer models, including those of breast, 9 bladder, 10 prostate, 11 lung 12 and liver, 13,14 and hematopoietic malignancies. 15 This antitumor activity of FTY720 is reportedly attributed to its cytotoxicity towards cancer cells through both caspase-dependent and caspase-independent apoptotic pathways. It is notable that in most instances phosphorylation of FTY720 was not required for its cytotoxic effect, indicating the involvement of S1P receptor-independent mechanisms which are starkly different from the immunosuppresive property of FTY720.…”

Effects of Phosphorylation of Immunomodulatory Agent FTY720 (Fingolimod) on Antiproliferative Activity against Breast and Colon Cancer Cells

“…15) The cells incubated with FTY720 demonstrated features characteristic of apoptosis. However, the association between the phosphorylation of FTY720 and its cytotoxicity against cancer cells is not clear.…”

BCR/ABL, mRNA translation and apoptosis

“…It has been shown that PP2A, a phosphatase with tumor suppressor activity, 58 regulates cell proliferation survival and differentiation 59,60 by inhibiting at post translational levels the function of mitogenic, anti-and/or proapoptotic and differentiation factors, including the BCR/ ABL-activated Akt and S6 kinases. [61][62][63][64] Since in CD34 þ CML blast crisis cells PP2A activity is impaired by increased levels of BCR/ABL oncogenic kinase (Neviani et al, 2005; manuscript submitted), inhibition of PP2A activity may represent another mechanism by which BCR/ABL sustains and enhances the PI-3K/Akt/mTOR/S6K-dependent efficiency of the translation machinery. Figure 1 Effect of BCR/ABL on the translational machinery.…”