Cell autonomous angiotensin II signaling controls the pleiotropic functions of oncogenic K-Ras

J Biol Chem. 2021 Jan-Jun:296:100242. doi: 10.1074/jbc.RA120.015188. Epub 2021 Jan 8.

Abstract

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.

Keywords: Ras; angiotensin; caveolin; oncogene; senescence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / genetics
  • Angiotensin II / metabolism
  • Angiotensinogen / genetics*
  • Angiotensinogen / metabolism
  • Animals
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Hypertension / drug therapy
  • Hypertension / genetics
  • Hypertension / pathology
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / innervation
  • Kruppel-Like Factor 6 / genetics*
  • Losartan / pharmacology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Oxidative Stress / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Receptor, Angiotensin, Type 1 / genetics*
  • Renin-Angiotensin System / genetics
  • STAT3 Transcription Factor / genetics

Substances

  • AGT protein, human
  • AGTR1 protein, human
  • Kruppel-Like Factor 6
  • Receptor, Angiotensin, Type 1
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Angiotensinogen
  • Angiotensin II
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • Losartan