Introduction Altered cell proliferation is critical to the progression of neoplastic disorders such as cancer and polycystic diseases. Identifying new potential therapeutic agents to target cell proliferation may therefore provide improved treatments for these disorders. Here, we used the simple, tractable biomedical model Dictyostelium to investigate the molecular mechanism of naringenin, a dietary flavonoid with antiproliferative and chemopreventive actions in vitro and in animal models of carcinogenesis [1,2]. Methods and Results Dictyostelium discoideum cells (wild type Ax2) were grown in liquid culture. Naringenin inhibited Dictyostelium growth, but not development, after 48-96 hours with an EC50 of 50-100 μM. Screening of a library of random gene knockout mutants identified a mutant (pkd2-) lacking the polycystin-2 protein (DDB_G0272999) that was resistant to the effect of naringenin (200 μM, 21 days) on growth and random cell movement. Naringenin (100 μM) reduced cell growth by 37% in wild type cells at 48 and 72 hours, but had no significant effect in the gene knockout mutant pkd2-. Polycystin-2 is a divalent cation channel, where mutations in the protein give rise to type 2 autosomal dominant polycystic kidney disease [3]. We therefore translated these results to a mammalian kidney model and grew Madin-Darby Canine Kidney (C7) cells in culture and as cysts in a collagen matrix [4]. Data are expressed as mean ± SEM from 3 independent experiments. Naringenin inhibited MDCK cell growth as measured by neutral red and SRB protein assay with an EC50 of 28 ± 1 μM and inhibited cyst growth with an EC50 of 3-10 μM. Levels of polycystin-2 protein were knocked down to 56 ± 5% after 24 and 48 hours by siRNA in this model. Polycystin-2 knockdown increased the EC50 value for naringenin in MDCK cells to 65 ± 1 μM. Cysts were larger following polycystin-2 knockdown compared to untransfected controls and resistant to the same concentration of naringenin: e.g. 10 μM naringenin: control 0.84 ± 0.03 mm2; polycystin-2 knockdown 1.44 ± 0.07 mm2; 30 μM naringenin: control 0.65 ± 0.01 mm2, polycystin-2 knockdown 1.18 ± 0.06 mm2. Metformin (10 μM), an activator of AMP-activated kinase and inhibitor of mTOR, reduced the size of both control and transfected cysts equally. Conclusion The antiproliferative actions of naringenin in Dictyostelium and mammalian kidney cells suggested a conserved effect of naringenin on cell growth mediated by polycystin-2. Further studies will determine if naringenin is a drug candidate for the treatment of ADPKD where polycystin-1 is lost but polycystin-2 is intact [5].