Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities

The antitumorigenic activity of nonsteroidal anti-inflammatory drugs (NSAID s), cyclooxygenase (COX) inhibitors, is well established, but responsible m olecular mechanisms are not fully understood. NSAIDs stimulate apoptosis by COX dependent and independent mechanisms in colorectal cells in culture. I dentification of genes regulated by COX inhibitors could lead to a better u nderstanding of their proapoptotic and anti-neoplastic activities. Using su btractive hybridization, a cDNA which was designated as NSAID activated gen e (NAG-1) was identified from NSAID-treated HCT-116, human colorectal cells . NAG-1 has an identical sequence with a novel member of the TGF-beta super family that has 5 different names. In the HCT-116 cells, NAG-1 expression i s increased and apoptosis is induced by treatment with some NSAIDs in a con centration and time-dependent manner. NAG-1 transfected cells exhibited inc reased basal apoptosis, increased response to NSAIDs and reduced soft agar cloning efficiency. Furthermore, transplantable tumors derived from NAG-1 t ransfected HCT-116 cells showed reduced tumorigenicity in athymic nude mice compared with vector-transfected HCT-116 cells. The increased NAG-1 expres sion by NSAIDs provides a suitable explanation for COX-independent apoptoti c effects of NSAIDs in cultured cells. These data demonstrate that NAG-1 is an antitumorigenic and proapoptotic protein, and its regulation by COX inh ibitors may provide new clues for explaining their proapoptotic and antitum origenic activities.