CDK4 Regulates Lysosomal Function and mTORC1 Activation to Promote Cancer Cell Survival.

Details

Ressource 1Request a copy Sous embargo indéterminé.
State: Public
Version: author
License: Not specified
Serval ID
serval:BIB_A55F9416C381
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
CDK4 Regulates Lysosomal Function and mTORC1 Activation to Promote Cancer Cell Survival.
Journal
Cancer research
Author(s)
Martínez-Carreres L., Puyal J., Leal-Esteban L.C., Orpinell M., Castillo-Armengol J., Giralt A., Dergai O., Moret C., Barquissau V., Nasrallah A., Pabois A., Zhang L., Romero P., Lopez-Mejia I.C., Fajas L.
ISSN
1538-7445 (Electronic)
ISSN-L
0008-5472
Publication state
Published
Issued date
15/10/2019
Peer-reviewed
Oui
Volume
79
Number
20
Pages
5245-5259
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Cyclin-dependent kinase 4 (CDK4) is well-known for its role in regulating the cell cycle, however, its role in cancer metabolism, especially mTOR signaling, is undefined. In this study, we established a connection between CDK4 and lysosomes, an emerging metabolic organelle crucial for mTORC1 activation. On the one hand, CDK4 phosphorylated the tumor suppressor folliculin (FLCN), regulating mTORC1 recruitment to the lysosomal surface in response to amino acids. On the other hand, CDK4 directly regulated lysosomal function and was essential for lysosomal degradation, ultimately regulating mTORC1 activity. Pharmacologic inhibition or genetic inactivation of CDK4, other than retaining FLCN at the lysosomal surface, led to the accumulation of undigested material inside lysosomes, which impaired the autophagic flux and induced cancer cell senescence in vitro and in xenograft models. Importantly, the use of CDK4 inhibitors in therapy is known to cause senescence but not cell death. To overcome this phenomenon and based on our findings, we increased the autophagic flux in cancer cells by using an AMPK activator in combination with a CDK4 inhibitor. The cotreatment induced autophagy (AMPK activation) and impaired lysosomal function (CDK4 inhibition), resulting in cell death and tumor regression. Altogether, we uncovered a previously unknown role for CDK4 in lysosomal biology and propose a novel therapeutic strategy to target cancer cells. SIGNIFICANCE: These findings uncover a novel function of CDK4 in lysosomal biology, which promotes cancer progression by activating mTORC1; targeting this function offers a new therapeutic strategy for cancer treatment.
Keywords
Adenylate Kinase/metabolism, Aminopyridines/pharmacology, Aminopyridines/therapeutic use, Animals, Autophagosomes/physiology, Autophagy/physiology, Benzimidazoles/pharmacology, Benzimidazoles/therapeutic use, Cell Line, Tumor, Cellular Senescence/physiology, Cyclin-Dependent Kinase 4/antagonists & inhibitors, Cyclin-Dependent Kinase 4/genetics, Cyclin-Dependent Kinase 4/physiology, Drug Synergism, Female, Gene Knockout Techniques, Humans, Insulin/physiology, Lysosomes/physiology, Lysosomes/ultrastructure, Mechanistic Target of Rapamycin Complex 1/metabolism, Mice, Mice, Inbred NOD, Molecular Targeted Therapy, Neoplasm Proteins/physiology, Phosphorylation, Protein Kinase Inhibitors/pharmacology, Protein Kinase Inhibitors/therapeutic use, Protein Processing, Post-Translational, Protein Transport, Proto-Oncogene Proteins/metabolism, Pyrones/pharmacology, Pyrones/therapeutic use, Recombinant Fusion Proteins/metabolism, Signal Transduction/physiology, Thiophenes/pharmacology, Thiophenes/therapeutic use, Tumor Suppressor Proteins/metabolism, Xenograft Model Antitumor Assays
Pubmed
Web of science
Funding(s)
Swiss National Science Foundation / 310030_182332
Swiss National Science Foundation / 310030-163064
Swiss National Science Foundation / 31003A-159586
Swiss National Science Foundation / PZ00P3_168077
Create date
06/01/2020 10:45
Last modification date
01/08/2020 5:19
Usage data