Cytosolic Cα²⁺ is an important regulator of tumor cell proliferation and metastasis. Recently, the strategy of blocking receptors and channels specific to certain cancer cell types has emerged as a potentially viable future treatment. Oral squamous cell carcinoma is an aggressive form of cancer with a high metastasis rate but the receptor-mechanisms involved in Cα²⁺ signaling in these tumors have not yet been elucidated. In our present study, we report that bradykinin induces Cα²⁺ signaling and its modulation in the human oral squamous carcinoma cell line, HSC-3. Bradykinin was found to increase the cytosolic Cα²⁺ levels in a concentration-dependent manner. This increase was inhibited by pretreatment with the phospholipase C-β inhibitor, U73122, and also by 2-aminoethoxydiphenyl borate, an inhibitor of the inositol 1,4,5-trisphosphate receptor. Pretreatment with extracellular ATP also inhibited the peak bradykinin-induced Cα²⁺ rise. In contrast, the ATP-induced rise in cytosolic Cα²⁺ was not affected by pretreatment with bradykinin. Pretreatment of the cells with either forskolin or phorbol 12-myristate 13-acetate (activators of adenylyl cyclase and protein kinase C, respectively) prior to bradykinin application accelerated the recovery of cytosolic Cα²⁺ to baseline levels. These data suggest that bradykinin receptors are functional in Cα²⁺ signaling in HSC-3 cells and may therefore represent a future target in treatment strategies for human oral squamous cell carcinoma.