Increased activity of the angiotensin converting enzyme C‐domain reduces melanoma growth by stimulating M1 macrophage polarization

Abstract

ACE is composed of two independent catalytic domains. To investigate the specific role of each ACE domain in tumor resistance, we made transgenic mice which over express in myeloid cells either wild type ACE (Tg‐ACE mice) or ACE lacking N‐ or C‐domain catalytic activity (Tg‐NKO and Tg‐CKO mice). Tg‐ACE and Tg‐NKO mice strongly suppressed the growth of B16‐F10 melanoma due to increased ACE expression by macrophages. In contrast, Tg‐CKO mice resist melanoma no better than wild type animals. The effect of ACE over expression reverts to wild type with an ACE inhibitor but not with an AT1 receptor antagonist. Over expression of the ACE C‐domain in macrophages drives cells towards a pronounced M1 phenotype upon tumor stimulation, with increased activation of NF‐kB and STAT1, and decreased activation of STAT3 and STAT6. TNFα is important in M1 activation of macrophages; TNFα blockade reverted Tg‐NKO macrophages to a wild type phenotype. Increased ACE C‐domain expression induced increased levels of the transcription factor C / EBPβ in macrophages, an important stimulus for TNFα expression. In contrast, there was decreased expression of IL‐4Rα, a key receptor for M2 activation of macrophages. Natural ACE C‐domain specific substrates are not well described. Nonetheless, the peptide(s) responsible for the ACE‐mediated enhancement of myeloid function are substrates and products of only the ACE C‐domain.Support or Funding InformationThis study was supported by NIH grant P01HL129941 (KEB), AI143599 (KEB), R21AI114965 (KEB), R01HL142672 (JFG), P30DK063491 (JFG), AHA grant 17GRNT33661206 (KEB), and AHA grant 16SDG30130015 (JFG).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.