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

Abstract

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