Cell autonomous angiotensin II signaling controls the pleiotropic functions of oncogenic K-Ras
| Autor: | Daniela Volonte, Victoria E. Cespedes, Morgan Sedorovitz, Ferruccio Galbiati, Maria Beecher |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Lung Neoplasms senescence Angiotensinogen NSCLC non–small-cell lung cancer Biochemistry KLF6 Kruppel-like factor 6 NHBE normal human bronchial epithelial Kidney Tubules Proximal Renin-Angiotensin System Mice oncogene Ang I angiotensin I STAT3 signal transducers and activators of transcription -3 STAT3 biology DPI diphenyleneiodonium chloride Chemistry Angiotensin II MEFs mouse embryonic fibroblasts Gene Expression Regulation Neoplastic ChIP chromatin immunoprecipitation KLF6 Hypertension Signal transduction JAK Janus kinase Research Article STAT3 Transcription Factor Senescence ACE angiotensin-converting enzyme TPA tissue plasminogen activator Losartan Receptor Angiotensin Type 1 NOX2 nicotinamide adenine dinucleotide phosphate oxidase 2 Proto-Oncogene Proteins p21(ras) 03 medical and health sciences AGT angiotensinogen ROS reactive oxygen species Kruppel-Like Factor 6 HMGA1 high-mobility group AT-hook 1 Animals Humans Molecular Biology AT1-R Ang II receptor type 1 Ang II angiotensin II 030102 biochemistry & molecular biology Oncogene Cell growth Cell Biology angiotensin Oxidative Stress 030104 developmental biology OIS oncogene-induced senescence Cancer cell biology.protein Cancer research SA-β-gal senescence-associated β-galactosidase caveolin Ras |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Oncogenic K-Ras (K-RasG12V) promotes senescence in normal cells but fuels transformation of cancer cells after the senescence barrier is bypassed. The mechanisms regulating this pleiotropic function of K-Ras remain to be fully established and bear high pathological significance. We find that K-RasG12V activates the angiotensinogen (AGT) gene promoter and promotes AGT protein expression in a Kruppel-like factor 6–dependent manner in normal cells. We show that AGT is then converted to angiotensin II (Ang II) in a cell-autonomous manner by cellular proteases. We show that blockade of the Ang II receptor type 1 (AT1-R) in normal cells inhibits oncogene-induced senescence. We provide evidence that the oncogenic K-Ras–induced synthesis of Ang II and AT1-R activation promote senescence through caveolin-1–dependent and nicotinamide adenine dinucleotide phosphate oxidase 2–mediated oxidative stress. Interestingly, we find that expression of AGT remains elevated in lung cancer cells but in a Kruppel-like factor 6–independent and high-mobility group AT-hook 1–dependent manner. We show that Ang II–mediated activation of the AT1-R promotes cell proliferation and anchorage-independent growth of lung cancer cells through a STAT3-dependent pathway. Finally, we find that expression of AGT is elevated in lung tumors of K-RasLA2-G12D mice, a mouse model of lung cancer, and human lung cancer. Treatment with the AT1-R antagonist losartan inhibits lung tumor formation in K-RasLA2-G12D mice. Together, our data provide evidence of the existence of a novel cell-autonomous and pleiotropic Ang II–dependent signaling pathway through which oncogenic K-Ras promotes oncogene-induced senescence in normal cells while fueling transformation in cancer cells. |
| Databáze: | OpenAIRE |
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