Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

Abstract

This study investigated Polo-like kinase 1, a mitotic regulator often over-expressed in solid tumors and adult hematopoietic malignancies, as a potential new target in the treatment of pediatric acute lymphoblastic leukemia. Polo-like kinase 1 protein and Thr210 phosphorylation levels were higher in pediatric acute lymphoblastic leukemia (n=172) than in normal bone marrow mononuclear cells (n=10) (P<0.0001). High Polo-like kinase 1 protein phosphorylation, but not expression, was associated with a lower probability of event-free survival (P=0.042) and was a borderline significant prognostic factor (P=0.065) in a multivariate analysis including age and initial white blood cell count. Polo-like kinase 1 was necessary for leukemic cell survival, since short hairpin-mediated Polo-like kinase 1 knockdown in acute lymphoblastic leukemia cell lines inhibited cell proliferation by G2/M cell cycle arrest and induced apoptosis through caspase-3 and poly (ADP-ribose) polymerase cleavage. Primary patient cells with a high Polo-like kinase 1 protein expression were sensitive to the Polo-like kinase 1-specific inhibitor NMS-P937 in vitro, whereas cells with a low expression and normal bone marrow cells were resistant. This sensitivity was likely not caused by Polo-like kinase 1 mutations, since only one new mutation (Ser335Arg) was found by 454-sequencing of 38 pediatric acute lymphoblastic leukemia cases. This mutation did not affect Polo-like kinase 1 expression or NMS-P937 sensitivity. Together, these results indicate a pivotal role for Polo-like kinase 1 in pediatric acute lymphoblastic leukemia and show potential for Polo-like kinase 1-inhibiting drugs as an addition to current treatment strategies for cases expressing high Polo-like kinase 1 levels. ABSTRACTinhibitor highly selective for PLK1 and the first orally administered selective PLK1 inhibitor entering phase I clinical trials 25 (clinicaltrials.gov identifier: NCT01014429). This study shows the potential of PLK1-targeting therapeutics in the treatment of childhood ALL, and indicates their value for further clinical evaluation. Methods Cell linesCell lines (DSMZ, Braunschweig, Germany) were cultured in RPMI+Glutamax with pen-strep, fungizone (Life Technologies, Bleiswijk, The Netherlands) and 10% or 20% fetal calf serum (Integro, Zaandam, The Netherlands), at 37ºC and 5% CO 2 .

Therapeutic targeting of Polo-like kinase-1 and Aurora kinases in T-cell acute lymphoblastic leukemia

“…9 As far as malignant blood disorders are concerned, PLK1 is expressed at high levels in chronic myelogenous leukemia (CML), 10 acute myelogenous leukemia (AML), 11 and acute lymphoblastic leukemia (ALL). 12 Overexpression of AK-A and -B has polo-like kinases (pLKs) and Aurora kinases (AKs) act as key cell cycle regulators in healthy human cells. In cancer, these protein kinases are often overexpressed and dysregulated, thus contributing to uncontrolled cell proliferation and growth.…”

The MicroRNA3686 Inhibits the Proliferation of Pancreas Carcinoma Cell Line by Targeting the Polo-Like Kinase 1

“…In particular, in addition to inhibition of cell proliferation, pancreas cancer cell transfected with mir3686 demonstrated enhanced apoptosis. Several reports had documented that inhibition of PLK1 in variety cancer cell lines could result in growth reduction and induce apoptosis [ 27 , 28 ]; however, the detailed mechanism of how PLK1 interaction with the cellular apoptosis pathway is still known and needs further investigation. In addition to a previous report that demonstrated that overexpression of PLK1 had been observed in the early stage of pancreas cancer, our data suggested that PLK1 might be a promising target for the treatment of pancreas cancer.…”

Polo‐like kinase and its inhibitors: Ready for the match to start?

“…A large number of pediatric acute lymphoblastic leukemia (ALL) samples were evaluated for Plk1 expression and responsiveness to NMS‐P937. Compared to normal bone marrow controls, pediatric ALL had higher Plk1 expression and was more sensitive to inhibition with NMS‐P937 . Other studies have shown its anti‐proliferative effects in a wide array of solid tumor and hematologic malignancies cell lines .…”