PLK1 (polo like kinase 1) inhibits MTOR complex 1 and promotes autophagy

Autophagy. 2017 Mar 4;13(3):486-505. doi: 10.1080/15548627.2016.1263781. Epub 2017 Jan 19.

Abstract

Mechanistic target of rapamycin complex 1 (MTORC1) and polo like kinase 1 (PLK1) are major drivers of cancer cell growth and proliferation, and inhibitors of both protein kinases are currently being investigated in clinical studies. To date, MTORC1's and PLK1's functions are mostly studied separately, and reports on their mutual crosstalk are scarce. Here, we identify PLK1 as a physical MTORC1 interactor in human cancer cells. PLK1 inhibition enhances MTORC1 activity under nutrient sufficiency and in starved cells, and PLK1 directly phosphorylates the MTORC1 component RPTOR/RAPTOR in vitro. PLK1 and MTORC1 reside together at lysosomes, the subcellular site where MTORC1 is active. Consistent with an inhibitory role of PLK1 toward MTORC1, PLK1 overexpression inhibits lysosomal association of the PLK1-MTORC1 complex, whereas PLK1 inhibition promotes lysosomal localization of MTOR. PLK1-MTORC1 binding is enhanced by amino acid starvation, a condition known to increase autophagy. MTORC1 inhibition is an important step in autophagy activation. Consistently, PLK1 inhibition mitigates autophagy in cancer cells both under nutrient starvation and sufficiency, and a role of PLK1 in autophagy is also observed in the invertebrate model organism Caenorhabditis elegans. In summary, PLK1 inhibits MTORC1 and thereby positively contributes to autophagy. Since autophagy is increasingly recognized to contribute to tumor cell survival and growth, we propose that cautious monitoring of MTORC1 and autophagy readouts in clinical trials with PLK1 inhibitors is needed to develop strategies for optimized (combinatorial) cancer therapies targeting MTORC1, PLK1, and autophagy.

Keywords: BI2536; MTOR; MTORC1; PLK1; RPTOR; amino acid; insulin; interphase; lysosome; starvation.

MeSH terms

  • Amino Acids / deficiency
  • Amino Acids / metabolism
  • Animals
  • Autophagy*
  • Biomarkers / metabolism
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Interphase
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mitosis
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / metabolism*
  • Regulatory-Associated Protein of mTOR / metabolism
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Amino Acids
  • Biomarkers
  • Caenorhabditis elegans Proteins
  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • RPTOR protein, human
  • Regulatory-Associated Protein of mTOR
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • plk-1 protein, C elegans