Cell-autonomous complement C3 maintains prostate epithelial cell homeostasis and prevents malignant transformation

Abstract Intracellularly active complement C3 and C3a emerged as central regulators of normal immune cell function proliferation via control mTOR glycolysis. Because increased glycolysis is a hallmark many cancer cells, we hypothesized that augmented cell-intrinsic activity may contribute to epithelial malignancy. However, while benign prostate cells (PECs) harbored expected intracellular C3/C3a storages, cancerous PECs, surprisingly, exhibited loss C3/C3a. Further, reduction levels in PECs correlated inversely with worsening Gleason scores patients, silencing healthy induced uncontrolled proliferation, reconstitution line DU145 normalized their hyper-proliferation. In an unexpected anti-proliferative role for C3ar−/−mice developed spontaneous hyperplasia tubular age, treatment tumors, implanted subcutaneously into the flanks athymic mice, C3a-expressing adenovirus significantly reduced tumor growth vivo, are associated better prognosis patients other types cancers. RNA-sequencing C3or C3aR-deficient human identified intrinsic novel controller several known PEC oncogenes, likely up-stream impact on c-MYC pathway. sum, drives (prostate) cell-autonomous negative regulator growths and, thus, represses oncogenic transformation. Such cell-specific activities should be taken consideration when targeting this system therapeutically.