With a special interest towards a better understanding of signal pathways, we attempted to discover a safer and more effective therapeutic strategy for kidney carcinoma. Recent studies had suggested a role mediated by PKCα for netrin-1 and its receptors in the initiation and progression of tumors. Real-time PCR and western blotting were used to determine the expression levels of netrin-1 and UNC5B. We made use of the agonist of PKCα (phorbol-12-myristate 13-acetate-PMA) and the inhibitor of PKCα (calphostin C) to treat renal cell carcinoma (RCC) cells, and MTT assays were used to measure cell proliferation. By immunofluorescence, we identified the localization of netrin-1 and UNC5B in RCC cell lines 769-P and ACHN. The expression of UNC5B in tumor tissues was significantly downregulated compared to the corresponding normal tissues in which netrin-1 was upregulated. In low grade tumors, UNC5B expression was more prominent while netrin-1 expression was the opposite when compared with high grade ones. Proliferation of ACHN cells was concentration dependent in the presence of PMA and calphostin C. Netrin-1 and UNC5B expressions were upregulated in cells treated with PMA while calphostin C reversed this upregulation. By immunofluorescence, we identified that netrin-1 was highly expressed in the nuclear but none of UNC5B. Our data highly suggested that PMA-induced upregulation and calphostin C-induced reversion of netrin-1 and UNC5B in kidney carcinoma were accompanied by the activation of the netrin-1/UNC5B pathways.