Polo-like kinase-1 as a novel target in neoplastic mast cells: demonstration of growth-inhibitory effects of small interfering RNA and the Polo-like kinase-1 targeting drug BI 2536.
BACKGROUND
In advanced systemic mastocytosis the response of neoplastic mast cells to conventional drugs is poor and the prognosis is bad. Current research is, therefore, attempting to identify novel drug targets in neoplastic mast cells. Polo-like kinase-1 is a serine/threonine kinase that plays an essential role in mitosis and has recently been introduced as a new target in myeloid leukemias and solid tumors.


METHODS
In the present study, we analyzed the expression and function of Polo-like kinase-1 in neoplastic mast cells in systemic mastocytosis.


RESULTS
As determined by immunostaining, primary neoplastic mast cells as well as the human mast cell leukemia cell line HMC-1 displayed phosphorylated Polo-like kinase-1. In addition, neoplastic mast cells expressed Polo-like kinase-1 mRNA. Polo-like kinase-1-specific small interfering RNA induced apoptosis in neoplastic mast cells, whereas no effect was seen with a control small interfering RNA. BI 2536, a drug targeting Polo-like kinase-1, was found to inhibit proliferation in HMC-1 cells in a dose-dependent manner. BI 2536 also inhibited the growth of primary neoplastic mast cells and cells of the canine mastocytoma cell line C2. The growth-inhibitory effects of BI 2536 on neoplastic mast cells were found to be associated with mitotic arrest and subsequent apoptosis. Finally, BI 2536 was found to synergize with the KIT-targeting kinase inhibitor midostaurin (PKC412) in inhibiting the growth of neoplastic mast cells. In control experiments, BI 2536 did not induce apoptosis in normal cultured mast cells.


CONCLUSIONS
Collectively, our data show that Polo-like kinase-1 is a potential therapeutic target in neoplastic mast cells. Targeting Polo-like kinase-1 may be an attractive pharmacological concept in the management of advanced systemic mastocytosis.
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria.
Barbara
B
Peter
Karoline V
KV
Gleixner
Sabine
S
Cerny-Reiterer
Harald
H
Herrmann
Viviane
V
Winter
Emir
E
Hadzijusufovic
Veronika
V
Ferenc
Karina
K
Schuch
Irina
I
Mirkina
Hans-Peter
HP
Horny
Winfried F
WF
Pickl
Leonhard
L
Müllauer
Michael
M
Willmann
Peter
P
Valent
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D007150:Immunohistochemistry; D020014:K562 Cells; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011621:Pteridines / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013936:Thymidine / Q000378:metabolism / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D013936:Thymidine; D000097869:Polo-Like Kinase 1; C518477:BI 2536
Leuk Res. 2001 Jul;25(7):603-25
11377686
Eur J Clin Invest. 2004 Aug;34 Suppl 2:41-52
15291805
Blood. 2006 Jul 1;108(1):286-91
16434489
J Histochem Cytochem. 1981 Apr;29(4):577-80
6166661
Oncology. 2008;74(1-2):96-103
18547964
Am J Respir Cell Mol Biol. 1990 Nov;3(5):413-20
2121170
Int Arch Allergy Immunol. 2002 Feb;127(2):110-4
11919418
Curr Biol. 2007 Feb 20;17(4):304-15
17291761
J Allergy Clin Immunol. 2009 Sep;124(3):514-21
19541349
Eur J Pharmacol. 2008 Sep 4;591(1-3):102-5
18616938
Anticancer Drug Des. 2000 Feb;15(1):17-28
10888033
Nat Rev Cancer. 2006 Apr;6(4):321-30
16557283
Br J Haematol. 2001 May;113(2):357-64
11380399
Leuk Res. 2003 Jul;27(7):635-41
12681363
Exp Hematol. 2003 Aug;31(8):686-92
12901973
Curr Opin Hematol. 2004 Jan;11(1):58-64
14676628
Immunol Lett. 2007 Apr 15;109(2):120-8
17368811
Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1609-14
9990072
J Immunol. 2008 Apr 15;180(8):5466-76
18390729
Anat Histol Embryol. 2002 Aug;31(4):214-23
12196263
Nat Genet. 1996 Mar;12(3):312-4
8589724
Ann Hematol. 2002 Dec;81(12):677-90
12483363
Oncogene. 2005 Jan 10;24(2):287-91
15640844
Leuk Res. 2001 Jul;25(7):543-51
11377679
Oncogene. 2007 Aug 23;26(39):5793-807
17369857
Wien Klin Wochenschr. 1996;108(13):385-97
8766423
Oncogene. 2005 Jan 10;24(2):267-76
15640842
Blood. 1989 May 15;73(7):1778-85
2469499
Blood. 2002 Mar 1;99(5):1741-4
11861291
Adv Enzyme Regul. 1984;22:27-55
6382953
J Clin Invest. 1993 Oct;92(4):1736-44
7691885
Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10560-4
7479840
Vet Immunol Immunopathol. 2007 Feb 15;115(3-4):320-33
17196258
Blood. 2005 Jul 15;106(2):721-4
15790786
Leuk Res. 1988;12(4):345-55
3131594
Curr Opin Hematol. 2010 Mar;17(2):125-32
20075725
Blood. 2005 Oct 15;106(8):2865-70
15972446
Cancer Res. 2010 Feb 15;70(4):1513-23
20145140
J Invest Dermatol. 1991 Mar;96(3):2S-4S
2002248
Blood. 2007 Jul 15;110(2):661-9
17420286
Br J Haematol. 2003 Sep;122(5):695-717
12930381
Annu Rev Med. 2004;55:419-32
14746529
Blood. 2009 Jun 4;113(23):5727-36
19363219
Curr Biol. 2007 Feb 20;17(4):316-22
17291758
J Pathol. 1993 Oct;171(2):83-98
7506771
Blood. 2009 Jul 16;114(3):659-62
19458358
Exp Hematol. 2008 Nov;36(11):1461-70
18723263
Blood. 2006 Jan 15;107(2):752-9
16189265