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

Mol Cell. 2016 Nov 3;64(3):493-506. doi: 10.1016/j.molcel.2016.09.016. Epub 2016 Oct 20.

Abstract

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.

Keywords: ABT199; BI6727; Fbw7; Myc; PLK1; neuroblastoma; small cell lung carcinoma; targeted therapy; ubiquitination.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Drug Synergism
  • F-Box Proteins / genetics*
  • F-Box Proteins / metabolism
  • F-Box-WD Repeat-Containing Protein 7
  • Feedback, Physiological*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice, Nude
  • N-Myc Proto-Oncogene Protein / antagonists & inhibitors
  • N-Myc Proto-Oncogene Protein / genetics*
  • N-Myc Proto-Oncogene Protein / metabolism
  • Neuroblastoma / drug therapy
  • Neuroblastoma / genetics*
  • Neuroblastoma / mortality
  • Neuroblastoma / pathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Polo-Like Kinase 1
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pteridines / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Sulfonamides / pharmacology
  • Survival Analysis
  • Transcription, Genetic
  • Tumor Burden / drug effects
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • BCL2 protein, human
  • BI 6727
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pteridines
  • RNA, Small Interfering
  • Sulfonamides
  • Ubiquitin-Protein Ligases
  • Protein Serine-Threonine Kinases
  • venetoclax