Polo-like Kinase-1 Regulates Myc Stabilization and Activates a Feedforward Circuit Promoting Tumor Cell Survival.

MYCN amplification in human cancers predicts poor prognosis and resistance to therapy. However, pharmacological strategies that directly target N-Myc, the protein encoded by MYCN, remain elusive. Here, we identify a molecular mechanism responsible for reciprocal activation between Polo-like kinase-1 (PLK1) and N-Myc. PLK1 specifically binds to the SCFFbw7 ubiquitin ligase, phosphorylates it, and promotes its autopolyubiquitination and proteasomal degradation, counteracting Fbw7-mediated degradation of N-Myc and additional substrates, including cyclin E and Mcl1. Stabilized N-Myc in turn directly activates PLK1 transcription, constituting a positive feedforward regulatory loop that reinforces Myc-regulated oncogenic programs. Inhibitors of PLK1 preferentially induce potent apoptosis of MYCN-amplified tumor cells from neuroblastoma and small cell lung cancer and synergistically potentiate the therapeutic efficacies of Bcl2 antagonists. These findings reveal a PLK1-Fbw7-Myc signaling circuit that underlies tumorigenesis and validate PLK1 inhibitors, alone or with Bcl2 antagonists, as potential effective therapeutics for MYC-overexpressing cancers.

Xiao D ，Yue M ，Su H ，Ren P ，Jiang J ，Li F ，Hu Y ，Du H ，Liu H ，Qing G ... -  《-》

Dual PLK1 and STAT3 inhibition promotes glioblastoma cells apoptosis through MYC.

Glioblastoma (GBM) is the deadliest primary brain tumor that is highly resistant to current treatments. Polo-like kinase 1 (PLK1) and signal transducer and activator of transcription 3 (STAT3) are highly expressed in gliomas, especially GBM. Previous studies have shown reciprocal activation between PLK1 and STAT3 and that they regulate the same pools of MYC downstream. We have demonstrated that PLK1 and STAT3 levels are elevated in gliomas compared with those in normal brain tissues, and high expression of both PLK1 and STAT3 is associated with poor prognosis in TCGA. Moreover, there was direct or indirect reciprocal regulation between PLK1 and STAT3. Furthermore, we found that PLK1 and STAT3 can regulate the same pools of MYC downstream. Compared to monotherapy, combined treatment of glioma cells with PLK1 and STAT3 inhibitors, BI2536 and Stattic, respectively, showed lower expression of MYC, synergistic induction of cell invasion and apoptosis in vitro, and tumor inhibition in xenografts. PLK1 and STAT3 were able to directly regulate the expression of MYC and induce apoptosis of glioma cells through the regulation of MYC. These findings may help develop a therapeutic strategy for dual inhibition of PLK1 and STAT3 against the tumorigenesis of glioma.

Wang H ，Tao Z ，Feng M ，Li X ，Deng Z ，Zhao G ，Yin H ，Pan T ，Chen G ，Feng Z ，Li Y ，Zhou Y ... -  《-》

The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models.

Pajtler KW ，Sadowski N ，Ackermann S ，Althoff K ，Schönbeck K ，Batzke K ，Schäfers S ，Odersky A ，Heukamp L ，Astrahantseff K ，Künkele A ，Deubzer HE ，Schramm A ，Sprüssel A ，Thor T ，Lindner S ，Eggert A ，Fischer M ，Schulte JH ... -  《Oncotarget》

SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction.

Inuzuka H ，Shaik S ，Onoyama I ，Gao D ，Tseng A ，Maser RS ，Zhai B ，Wan L ，Gutierrez A ，Lau AW ，Xiao Y ，Christie AL ，Aster J ，Settleman J ，Gygi SP ，Kung AL ，Look T ，Nakayama KI ，DePinho RA ，Wei W ... -  《-》

Reciprocal activation between PLK1 and Stat3 contributes to survival and proliferation of esophageal cancer cells.

Aberrant activation of the signal transducer and activator of transcription (Stat)3 and overexpression of polo-like kinase (PLK)1 each have been associated with cancer pathogenesis. The mechanisms and significance of dysregulation of Stat3 and PLK1 in carcinogenesis and cancer progression are unclear. We investigated the relationship between Stat3 and PLK1 and the effects of their dysregulation in esophageal squamous cell carcinoma (ESCC) cells. We used immunoblot, quantitative reverse-transcription polymerase chain reaction, immunochemistry, chromatin immunoprecipitation, mobility shift, and reporter assays to investigate the relationship between Stat3 and PLK1. We used colony formation, fluorescence-activated cell sorting, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and xenograft tumor assays to determine the effects of increased activation of Stat3 and PLK1 in proliferation and survival of ESCC cells. Stat3 directly activated transcription of PLK1 in esophageal cancer cells and mouse embryonic fibroblast cell NIH3T3. PLK1 then potentiated the expression of Stat3; β-catenin was involved in PLK1-dependent transcriptional activation of Stat3. This mutual regulation between Stat3 and PLK1 was required for proliferation of esophageal cancer cells and resistance to apoptosis in culture and as tumor xenografts in mice. Furthermore, phosphorylation of Stat3 and overexpression of PLK1 were correlated in a subset of ESCC. Stat3 and PLK1 control each other's transcription in a positive feedback loop that contributes to the development of ESCC. Increased activity of Stat3 and overexpression of PLK1 promote survival and proliferation of ESCC cells in culture and in mice.

Zhang Y ，Du XL ，Wang CJ ，Lin DC ，Ruan X ，Feng YB ，Huo YQ ，Peng H ，Cui JL ，Zhang TT ，Wang YQ ，Zhang H ，Zhan QM ，Wang MR ... -  《-》