Ruf Stefanie, Heberle Alexander Martin, Langelaar-Makkinje Miriam, Gelino Sara, Wilkinson Deepti, Gerbeth Carolin, Schwarz Jennifer Jasmin, Holzwarth Birgit, Warscheid Bettina, Meisinger Chris, van Vugt Marcel A T M, Baumeister Ralf, Hansen Malene, Thedieck Kathrin
a Department of Bioinformatics and Molecular Genetics, Faculty of Biology , University of Freiburg , Freiburg , Germany.
b Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases , University of Groningen, University Medical Center Groningen , AV Groningen , The Netherlands.
Autophagy. 2017 Mar 4;13(3):486-505. doi: 10.1080/15548627.2016.1263781. Epub 2017 Jan 19.
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.
雷帕霉素机制性靶标复合物1（MTORC1）和波罗蛋白样激酶1（PLK1）是癌细胞生长和增殖的主要驱动因素，目前这两种蛋白激酶的抑制剂正在临床研究中接受调查。迄今为止，MTORC1和PLK1的功能大多是分别进行研究的，关于它们相互串扰的报道很少。在此，我们确定PLK1是人类癌细胞中MTORC1的直接相互作用蛋白。在营养充足和饥饿的细胞中，PLK1抑制都会增强MTORC1的活性，并且PLK1在体外直接磷酸化MTORC1组分RPTOR/RAPTOR。PLK1和MTORC1共同定位于溶酶体，即MTORC1发挥活性的亚细胞位点。与PLK1对MTORC1的抑制作用一致，PLK1过表达会抑制PLK1-MTORC1复合物与溶酶体的结合，而PLK1抑制则会促进MTOR向溶酶体的定位。氨基酸饥饿会增强PLK1-MTORC1的结合，已知这种情况会增加自噬。MTORC1抑制是自噬激活的重要步骤。同样，PLK1抑制在营养饥饿和充足的情况下都会减轻癌细胞中的自噬，并且在无脊椎动物模式生物秀丽隐杆线虫中也观察到了PLK1在自噬中的作用。总之，PLK1抑制MTORC1，从而对自噬产生正向作用。由于自噬对肿瘤细胞存活和生长的作用越来越受到认可，我们建议在使用PLK1抑制剂的临床试验中谨慎监测MTORC1和自噬指标，以便制定针对MTORC1、PLK1和自噬的优化（联合）癌症治疗策略。
