(Pro)renin receptor ((P)RR), a receptor for renin and prorenin, is expressed in various types of normal and cancer cells. (P)RR is related to both the renin-angiotensin system and vacuolar H -ATPase (V-ATPase) (1). Binding of renin and prorenin to (P)RR stimulates the intracellular signaling pathways, including ERK 1/2. An inhibition of V-ATPase function caused inhibition of autophagy. We have previously reported expression of (P)RR in the tumor tissues of breast cancers and cultured human breast cancer cells (2). Suppression of (P)RR expression by (P)RR-specific siRNA decreased cell proliferation of cultured breast cancer cells, suggesting that (P)RR acts as a stimulating factor for cancer cell proliferation. However, the relationship of (P)RR with ERK phosphorylation and autophagy has not been clarified in cancer cells. The aim of the present study was therefore to clarify the relationship of (P)RR with ERK phosphorylation and autophagy in proliferation of cancer cells. The experiments were performed in MCF-7 human breast cancer cells, T47D human breast cancer cells and HepG2 human liver cancer cells. Cell proliferation was examined by the WST-8 method. The expression levels of (P)RR and autophagy-related proteins, LC3 and p62, and ERK phosphorylation were examined by western blot analysis. Each experiment was repeated at least 3 times. Statistical analysis was performed by ANOVA, followed by Tukey-Kramer test. Suppression of (P)RR expression using (P)RR-specific siRNA decreased cell proliferation in MCF-7, T47D and HepG2 cells (36%, 49% and 81% of control, respectively; p<0.0001 in all three cell lines, n=6). By suppressing the expression of (P)RR, phosphorylation of ERK was activated about 5-fold in MCF-7 cells, whereas it was suppressed in T47D and HepG2 cells (about 40% and 60% of control). Furthermore, the intracellular amount of LC3 and p62, autophagy-related proteins, increased by suppressing the expression of (P)RR in all three types of cell lines (LC3, about 2-3-fold; p62, about 1.3-1.5-fold), suggesting that autophagy was inhibited by suppression of the (P)RR expression, and LC3 and p62 accumulated in the cancer cells. These findings suggest that proliferation of cancer cells by (P)RR may be mediated by signaling pathways other than the ERK signaling, possibly the regulation of autophagy via the V-ATPase function.