TRAIL is a member of TNF family of ligands and binds to death receptor (DR) 4 and 5 to induce apoptosis selectively in cancer and transformed cells. Therefore, TRAIL has been thought of as a promising chemotherapeutic agent. However, some carcinomas become resistant to TRAIL. In carcinoma cells, the β4-integrin functions in a ligand-independent manner to promote proliferation, migration, and invasion. Furthermore, β4-integrin can also induce growth arrest and apoptosis in certain carcinomas. These observations suggest that β4-integrin signaling might cooperate with death signals in these carcinoma cells. Herein, we show that β4-integrin sensitizes MDA-MB-435 breast carcinomas and RKO rectal carcinomas to TRAIL-induced apoptosis in a dose-dependent and time-dependent manner and enhances TRAIL-induced processing of caspase-8 and caspase-3. Interestingly, we have observed that the potentiation of TRAIL-induced apoptosis by β4-integrin is due to an interaction between DR4 and DR5 with β4-integrin leading to the oligomerization and activation of these death receptors. Furthermore, the knock-down of β4-integrin in MDA-MB-231 cells attenuates TRAIL-induced apoptosis. These studies indicate a novel function of β4-integrin as an “amplifier” of death signaling in certain carcinoma cells. Moreover, the expression of β4-integrin on carcinomas may be used as a marker for their sensitivity to TRAIL-induced apoptosis. Thus, the interaction between an integrin receptor and death receptor may provide new therapeutic approaches in treatment of cancer.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]