The oral iron chelator deferasirox represses signaling through the mTOR in myeloid leukemia cells by enhancing expression of REDD1.
To evaluate the effect of deferasirox in human myeloid leukemia cells, and to identify the molecular pathways responsible for antiproliferative effects on leukemia cells during chelation therapy, we performed gene expression profiling to focus on the pathway involved in the anticancer effect of deferasirox. The inhibitory concentration (IC50) of deferasirox was 17-50 microM in three human myeloid cell lines (K562, U937, and HL60), while those in fresh leukemia cells obtained from four patients it varied from 88 to 172 microM. Gene expression profiling using Affymerix GeneChips (U133 Plus 2.0) revealed up-regulation of cyclin-dependent kinase inhibitor 1A (CDKN1A) encoding p21CIP, genes regulating interferon (i.e. IFIT1). Pathways related to iron metabolism and hypoxia such as growth differentiation factor 15 (GDF-15) and Regulated in development and DNA damage response (REDD1) were also prominent. Based on the results obtained from gene expression profiling, we particularly focused on the REDD1/mTOR (mammalian target of rapamycin) pathway in deferasirox-treated K562 cells, and found an enhanced expression of REDD1 and its down-stream protein, tuberin (TSC2). Notably, S6 ribosomal protein as well as phosphorylated S6, which is known to be a target of mTOR, was significantly repressed in deferasirox-treated K562 cells, and REDD1 small interfering RNA restored phosphorylation of S6. Although iron chelation may affect multiple signaling pathways related to cell survival, our data support the conclusion that REDD1 functions up-stream of tuberin to down-regulate the mTOR pathway in response to deferasirox. Deferasirox might not only have benefit for iron chelation but also may be an antiproliferative agent in some myeloid leukemias, especially patients who need both iron chelation and reduction of leukemia cells.
Ohyashiki
Junko H
JH
Intractable Diseases Therapeutic Research Center, Tokyo Medical University, Tokyo 160-0023, Japan. junko@hh.iij4u.or.jp
Kobayashi
Chiaki
C
Hamamura
Ryoko
R
Okabe
Seiichi
S
Tauchi
Tetsuzo
T
Ohyashiki
Kazuma
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077588:Deferasirox; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011494:Protein Kinases / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D001565:Benzoates; C469991:DDIT4 protein, human; D007502:Iron Chelating Agents; D038601:Ribosomal Protein S6; D014157:Transcription Factors; D014230:Triazoles; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000077588:Deferasirox