Plectin, a linker protein that organizes the cytoskeleton, is critical for cell migration and wound healing. It is specifically expressed in epithelial cells, muscles, and other tissues. Numerous studies have shown that curcumin (diferuloylmethane) has anti-cancer potential. Curcumin can inhibit cancer cell migration and invasion through various signaling pathways. In this study, the down-regulation of plectin expression by siRNA was observed to induce the migration and invasion of human breast and lung cancer cell lines. Interestingly, the down-regulation of plectin expression by siRNA reversed the curcumin-induced anti-migration and anti-invasion effects in both cancer cell lines while ${alpha}$-tocopherol and genistein inhibited knockdown of plectin induced cancer cell migration. Curcumin did not affect the expression of plectin; however, ${alpha}$-tocopherol and genistein inhibited migration in plectin down-regulated cancer cells. These findings support the novel role of plectin and its effect on the anti-migration and anti-invasion potential of curcumin.