Carfilzomib induces leukaemia cell apoptosis via inhibiting ELK1/KIAA1524 (Elk-1/CIP2A) and activating PP2A not related to proteasome inhibition.
Enhancing the tumour suppressive activity of protein phosphatase 2A (PP2A) has been suggested to be an anti-leukaemic strategy. KIAA1524 (also termed CIP2A), an oncoprotein inhibiting PP2A, is associated with disease progression in chronic myeloid leukaemia and may be prognostic in cytogenetically normal acute myeloid leukaemia. Here we demonstrated that the selective proteasome inhibitor, carfilzomib, induced apoptosis in sensitive primary leukaemia cells and in sensitive leukaemia cell lines, associated with KIAA1524 protein downregulation, increased PP2A activity and decreased p-Akt, but not with the proteasome inhibition effect of carfilzomib. Ectopic expression of KIAA1524, or pretreatment with the PP2A inhibitor, okadaic acid, suppressed carfilzomib-induced apoptosis and KIAA1524 downregulation in sensitive cells, whereas co-treatment with the PP2A agonist, forskolin, enhanced carfilzomib-induced apoptosis in resistant cells. Mechanistically, carfilzomib affected KIAA1524 transcription through disturbing ELK1 (Elk-1) binding to the KIAA1524 promoter. Moreover, the drug sensitivity and mechanism of carfilzomib in xenograft mouse models correlated well with the effects of carfilzomib on KIAA1524 and p-Akt expression, as well as PP2A activity. Our data disclosed a novel drug mechanism of carfilzomib in leukaemia cells and suggests the potential therapeutic implication of KIAA1524 in leukaemia treatment.
Comprehensive Breast Health Centre, Taipei Veterans General Hospital, Taipei, Taiwan.|Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Haematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Chun-Yu
CY
Liu
Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Feng-Shu
FS
Hsieh
Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan.|School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
Pei-Yi
PY
Chu
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
Wen-Chun
WC
Tsai
School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Haematology and Oncology, Department of Medicine, Yang-Ming Branch of Taipei City Hospital, Taipei, Taiwan.
Chun-Teng
CT
Huang
School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Haematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Yuan-Bin
YB
Yu
Comprehensive Breast Health Centre, Taipei Veterans General Hospital, Taipei, Taiwan.|Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
Tzu-Ting
TT
Huang
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Haematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Po-Shen
PS
Ko
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Haematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Man-Hsin
MH
Hung
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
Wan-Lun
WL
Wang
Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
Chung-Wai
CW
Shiau
Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.|National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
Kuen-Feng
0000-0002-4686-7019
KF
Chen
D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001324:Autoantigens / Q000378:metabolism; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation / Q000379:methods; D019319:Okadaic Acid / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009842:Oligopeptides; D011500:Protein Synthesis Inhibitors; D019319:Okadaic Acid; C524865:carfilzomib; D003513:Cycloheximide; D046988:Proteasome Endopeptidase Complex
KIAA1524; PP2A; apoptosis; carfilzomib; leukaemia