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mTOR Activation Initiates Renal Cell Carcinoma Development by Coordinating ERK and p38MAPK.
- Source :
-
Cancer research [Cancer Res] 2021 Jun 15; Vol. 81 (12), pp. 3174-3186. Date of Electronic Publication: 2021 Apr 16. - Publication Year :
- 2021
-
Abstract
- Renal cell carcinoma (RCC) mainly originates from renal proximal tubules. Intriguingly, disruption of genes frequently mutated in human RCC samples thus far has only generated RCC originated from other renal tubule parts in mouse models. This hampers our understanding of the pathogenesis of RCC. Here we show that mTOR signaling, often activated in RCC samples, initiates RCC development from renal proximal tubules. Ablation of Tsc1 , encoding an mTOR suppressor, in proximal tubule cells led to multiple precancerous renal cysts. mTOR activation increased MEK1 expression and ERK activation, and Mek1 ablation or inhibition diminished cyst formation in Tsc1 -deficient mice. mTOR activation also increased MKK6 expression and p38MAPK activation, and ablation of the p38α-encoding gene further enhanced cyst formation and led to RCC with clear cell RCC features. Mechanistically, Tsc1 deletion induced p53 and p16 expression in a p38MAPK-dependent manner, and deleting Tsc1 and Trp53 or Cdkn2a (encoding p16) enhanced renal cell carcinogenesis. Thus, mTOR activation in combination with inactivation of the p38MAPK-p53/p16 pathway drives RCC development from renal proximal tubules. Moreover, this study uncovers previously unidentified mechanisms by which mTOR controls cell proliferation and suggests the MEK-ERK axis to be a potential target for treatment of RCC. SIGNIFICANCE: Mouse modeling studies show that mTOR activation in combination with inactivation of the p38MAPK-p53/p16 axis initiates renal cell carcinoma that mimics human disease, identifying potential therapeutic targets for RCC treatment.<br /> (©2021 American Association for Cancer Research.)
- Subjects :
- Animals
Apoptosis
Carcinoma, Renal Cell etiology
Carcinoma, Renal Cell metabolism
Cell Proliferation
Gene Expression Regulation, Neoplastic
Kidney Neoplasms etiology
Kidney Neoplasms metabolism
Kidney Neoplasms pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation
TOR Serine-Threonine Kinases genetics
Tumor Cells, Cultured
Carcinoma, Renal Cell pathology
Cyclin-Dependent Kinase Inhibitor p16 physiology
MAP Kinase Kinase 1 physiology
Mitogen-Activated Protein Kinase 14 physiology
TOR Serine-Threonine Kinases metabolism
Tuberous Sclerosis Complex 1 Protein physiology
Tumor Suppressor Protein p53 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 81
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 33863779
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-20-3979