The overexpression of wild-type cysteine-rich 61 (Cyr61) is associated with the aggressiveness of cancer and poor prognosis in different human cancers. The aim of this study was to examine the expression of Cyr61 protein in prostate adenocarcinomas and to investigate the effects of inhibiting Cyr61 expression using small interfering RNA on the proliferation, migration, invasiveness, and sensitivity of prostate carcinoma PC-3 cells to TNF-related apoptosis-inducing ligand. Cell proliferation was measured by XTT assay. Colony formation assay, wound healing assay, and Matrigel invasion assay were also examined. Immunohistochemical staining of prostate tumor tissues showed that prostate carcinomas had significantly increased Cyr61 level compared with benign glands adjacent to carcinoma. siRNA-based knockdown of Cyr61 resulted in decreased cellular proliferation, clonogenicity, migration, and invasion. At the same time, Cyr61 silencing effectively reduced the levels of phosphorylated Akt and integrin-${eta}_3$. Cyr61-specific siRNA combined with TRAIL increased the apoptosis of PC-3 cells and the cleavage of apoptosis hallmarkers such as PARP and caspase-3. Taken together, our data provide evidence that Cyr61 modulates integrin-${eta}_3$ level as well as PI3-kinase/Akt activity through which Cyr61 may mediate tumorigenesis, and suggest the potential importance of Cyr61 targeting on enhancing the therapeutic efficacy of prostate cancer.