| First Author | Volonte D | Year | 2021 |
| Journal | J Biol Chem | Volume | 296 |
| Pages | 100242 | PubMed ID | 33380422 |
| Mgi Jnum | J:302979 | Mgi Id | MGI:6507497 |
| Doi | 10.1074/jbc.RA120.015188 | Citation | Volonte D, et al. (2021) Cell autonomous angiotensin II signaling controls the pleiotropic functions of oncogenic K-Ras. J Biol Chem :100242 |
| abstractText | Oncogenic K-Ras (K-Ras(G12V)) 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-Ras(G12V) activates the angiotensinogen (AGT) gene promoter and promotes AGT protein expression in a Kruppel Like Factor 6 (KLF6)-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 (OIS). We provide evidence that the oncogenic K-Ras-induced synthesis of Ang II and AT1-R activation promote senescence through caveolin-1-dependent and NOX2-mediated oxidative stress. Interestingly, we find that expression of AGT remains elevated in lung cancer cells but in a KLF6-independent and High Mobility Group AT-Hook 1 (HMGA1)-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-Ras(LA2-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-Ras(LA2-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 OIS in normal cells while fueling transformation in cancer cells. |
