%0 Journal Article %1 rufPLK1PoloKinase2017a %A Ruf, Stefanie %A Heberle, Alexander Martin %A Langelaar-Makkinje, Miriam %A Gelino, Sara %A Wilkinson, Deepti %A Gerbeth, Carolin %A Schwarz, Jennifer Jasmin %A Holzwarth, Birgit %A Warscheid, Bettina %A Meisinger, Chris %A van Vugt, Marcel A. T. M. %A Baumeister, Ralf %A Hansen, Malene %A Thedieck, Kathrin %C United States %D 2017 %J Autophagy %K & *Autophagy,amino 1,Protein 1/*metabolism,Mitosis,MTOR,MTORC1,Phosphorylation,PLK1,Polo-Like Acids/deficiency/metabolism,Animals,BI2536,Biomarkers/metabolism,Caenorhabditis Binding,Protein Cells,Humans,insulin,interphase,Interphase,lysosome,Lysosomes/metabolism,Mechanistic Complex Cycle Kinase Kinases/antagonists Kinases/metabolism Protein Proteins/*metabolism,Caenorhabditis Proteins/antagonists Rapamycin Serine-Threonine Target acid,Amino elegans elegans/metabolism,Cell inhibitors/*metabolism,HeLa inhibitors/*metabolism,Proto-Oncogene inhibitors/*metabolism,Regulatory-Associated mTOR/metabolism,RPTOR,starvation,to_read,TOR of %N 3 %P 486--505 %R 10.1080/15548627.2016.1263781 %T PLK1 (Polo like Kinase 1) Inhibits MTOR Complex 1 and Promotes Autophagy. %V 13 %X 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.

@article{rufPLK1PoloKinase2017a, 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.}, added-at = {2024-05-17T13:01:35.000+0200}, address = {United States}, author = {Ruf, Stefanie and Heberle, Alexander Martin and {Langelaar-Makkinje}, Miriam and Gelino, Sara and Wilkinson, Deepti and Gerbeth, Carolin and Schwarz, Jennifer Jasmin and Holzwarth, Birgit and Warscheid, Bettina and Meisinger, Chris and {van Vugt}, Marcel A. T. M. and Baumeister, Ralf and Hansen, Malene and Thedieck, Kathrin}, biburl = {https://www.bibsonomy.org/bibtex/2af9ea0de3e707e2cdbdeb6841bb68f3e/warscheidlab}, doi = {10.1080/15548627.2016.1263781}, interhash = {8a880ade737172eb22d428b448637ba7}, intrahash = {af9ea0de3e707e2cdbdeb6841bb68f3e}, issn = {1554-8635 1554-8627}, journal = {Autophagy}, keywords = {& *Autophagy,amino 1,Protein 1/*metabolism,Mitosis,MTOR,MTORC1,Phosphorylation,PLK1,Polo-Like Acids/deficiency/metabolism,Animals,BI2536,Biomarkers/metabolism,Caenorhabditis Binding,Protein Cells,Humans,insulin,interphase,Interphase,lysosome,Lysosomes/metabolism,Mechanistic Complex Cycle Kinase Kinases/antagonists Kinases/metabolism Protein Proteins/*metabolism,Caenorhabditis Proteins/antagonists Rapamycin Serine-Threonine Target acid,Amino elegans elegans/metabolism,Cell inhibitors/*metabolism,HeLa inhibitors/*metabolism,Proto-Oncogene inhibitors/*metabolism,Regulatory-Associated mTOR/metabolism,RPTOR,starvation,to_read,TOR of}, langid = {english}, month = mar, number = 3, pages = {486--505}, pmcid = {PMC5361591}, pmid = {28102733}, timestamp = {2024-05-17T13:01:35.000+0200}, title = {{{PLK1}} (Polo like Kinase 1) Inhibits {{MTOR}} Complex 1 and Promotes Autophagy.}, volume = 13, year = 2017 }