Phosphoproteomic studies of alamandine signaling in CHO‐MrgD and human pancreatic carcinoma cells: An antiproliferative effect is unveiled

Abstract Alamandine is a heptapeptide from the renin‐angiotensin system (RAS) with similar structure/function to angiotensin‐(1‐7) [ang‐(1‐7)], but they act via different receptors. It remains elusive whether alamandine is an antiproliferative agent like ang‐(1‐7). The goal of this study was to evaluate the potential antiproliferative activity of alamandine and the underlying cellular signaling. We evaluated alamandine effect in the tumoral cell lines Mia PaCa‐2 and A549, and in the nontumoral cell lines HaCaT, CHO and CHO transfected with the alamandine receptor MrgD (CHO‐MrgD). Alamandine was able to reduce the proliferation of the tumoral cell lines in a MrgD‐dependent fashion. We did not observe any effect in the nontumoral cell lines tested. We also performed proteomics and phosphoproteomics to study the alamandine signaling in Mia PaCa‐2 and CHO‐MrgD. Data suggest that alamandine induces a shift from anaerobic to aerobic metabolism in the tumoral cells, induces a negative regulation of PI3K/AKT/mTOR pathway and activates the transcriptional factor FoxO1; events that could explain, at least partially, the observed antiproliferative effect of alamandine. This study provides for the first time a comprehensive investigation of the alamandine signaling in tumoral (Mia PaCa‐2) and nontumoral (CHO‐MrgD) cells, highlighting the antiproliferative activity of alamandine/MrgD and its possible antitumoral effect.