Polo-like-kinase 1 (PLK1) as a molecular target to overcome SYK-mediated resistance of B-lineage acute lymphoblastic leukaemia cells to oxidative stress.
SYK tyrosine kinase has emerged as a master regulator of cellular resistance to oxidative stress (OS) by mediating the activation of the anti-apoptotic nuclear factor kappaB and phosphatidylinositol-3 kinase/AKT pathways after OS exposure. Here, we present unprecedented experimental evidence that polo-like kinase 1 (PLK1) is the upstream regulator of SYK in B-lineage acute lymphoblastic leukaemia (ALL) cells. Selective inhibition of PLK-1 with the leflunomide metabolite analogue alpha-cyano-beta-hydroxy-beta-methyl-N-[4-(trifluoromethoxy) phenyl]-propenamide/LFM-A12 abolished the resistance of B-lineage ALL cells to OS by preventing the activation of the anti-apoptotic SYK signal transduction pathway. Notably, LFM-A12 treatments at non-cytotoxic concentrations resulted in marked augmentation of clonogenic death in resistant human B-lineage ALL cell lines challenged with OS. Further, LFM-A12 augmented OS-induced apoptosis of chemotherapy-resistant primary leukaemic cells from relapsed B-lineage ALL patients in vitro and markedly potentiated the in vivo anti-leukaemic activity of total body irradiation (TBI) against leukaemia-initiating cells in severe combined immunodeficient mouse xenograft models of B-lineage ALL. This study is the first to identify PLK1 as a regulator of SYK tyrosine kinase and a molecular target to overcome SYK-mediated resistance of B-lineage ALL cells to OS.
Uckun
Fatih M
FM
Department of Pediatrics, University of Southern California Keck School of Medicine, USA. fmuckun@chla.usc.edu <fmuckun@chla.usc.edu>
Ozer
Zahide
Z
Qazi
Sanjive
S
Tuel-Ahlgren
Lisa
L
Mao
Chen
C
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002648:Child; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D018384:Oxidative Stress / Q000502:physiology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000072377:Syk Kinase; D055815:Young Adult; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; D000097869:Polo-Like Kinase 1; C000606896:SYK protein, human; C000606897:Syk protein, mouse