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Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation.
- Source :
-
Molecular & cellular proteomics : MCP [Mol Cell Proteomics] 2019 Jul; Vol. 18 (7), pp. 1330-1344. Date of Electronic Publication: 2019 Apr 22. - Publication Year :
- 2019
-
Abstract
- Rapidly proliferating cells reshape their metabolism to satisfy their ever-lasting need for cellular building blocks. This phenomenon is exemplified in certain malignant conditions such as cancer but also during embryonic development when cells rely heavily on glycolytic metabolism to exploit its metabolic intermediates for biosynthetic processes. How cells reshape their metabolism is not fully understood. Here we report that loss of cathepsin L (Cts L) is associated with a fast proliferation rate and enhanced glycolytic metabolism that depend on lactate dehydrogenase A (LDHA) activity. Using mass spectrometry analysis of cells treated with a pan cathepsin inhibitor, we observed an increased abundance of proteins involved in central carbon metabolism. Further inspection of putative Cts L targets revealed an enrichment for glycolytic metabolism that was independently confirmed by metabolomic and biochemical analyses. Moreover, proteomic analysis of Cts L-knockout cells identified LDHA overexpression that was demonstrated to be a key metabolic junction in these cells. Lastly, we show that Cts L inhibition led to increased LDHA protein expression, suggesting a causal relationship between LDHA expression and function. In conclusion, we propose that Cts L regulates this metabolic circuit to keep cell division under control, suggesting the therapeutic potential of targeting this protein and its networks in cancer.<br /> (© 2019 Weiss-Sadan et al.)
- Subjects :
- Animals
Cell Proliferation
Embryo, Mammalian cytology
Fibroblasts metabolism
Gene Deletion
Glycolysis
HeLa Cells
Humans
Lactate Dehydrogenase 5 genetics
Lactate Dehydrogenase 5 metabolism
Lipogenesis
Mass Spectrometry
Metabolomics
Mice
NIH 3T3 Cells
Phenotype
Proteomics
RNA, Messenger genetics
RNA, Messenger metabolism
Cathepsin L metabolism
Metabolic Networks and Pathways
Subjects
Details
- Language :
- English
- ISSN :
- 1535-9484
- Volume :
- 18
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Molecular & cellular proteomics : MCP
- Publication Type :
- Academic Journal
- Accession number :
- 31010818
- Full Text :
- https://doi.org/10.1074/mcp.RA119.001392