TRAIL 저항성 인간 방광암 세포에서 histone deacetylase 억제제인 Trichostatin A에 의한 TRAIL 매개 세포 사멸 유도의 증가 = Trichostatin A, a Histone Deacetylase Inhibitor, Enhances TRAIL-mediated Apoptosis in Human Bladder Carcinoma Cells

다국어 초록 (Multilingual Abstract)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that activates the death receptors (DRs)-mediated extrinsic apoptosis pathway by binding to DRs on the cell outer membrane. However, since many tumors ares already resistance to TRAIL, interest is increasing in combination therapies that overcome TRAIL resistance using TRAIL-sensitizing pharmacological agents. This study investigated whether trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, could increase sensitivity to TRAIL- mediated apoptosis in TRAIL-resistant T24 human bladder cancer cells. The results showed greater reduction of cell viability in the TRAIL+TSA combination treatment group than in the group treated with TRAIL or TSA alone, which was associated with enhanced apoptosis. Additionally, this combination therapy increased DR5 expression on the cell outer membrane surface, reduced the expression of Fas-associated death domain-like interleukin-1β-converting enzyme inhibitory protein long variant, and significantly activated extrinsic and intrinsic initiator caspases and effector caspase, accompanied by increased cleavage of poly(ADP-ribose) polymerase. This combination therapy also induced mitochondrial dysfunction, which led to cytochrome c release into the cytosol, while reducing Bcl-xL expression and increasing Bid truncation. Furthermore, the enhanced apoptosis involved disruption of the activity of the phosphoinositide 3-kinase/Akt and mitogen-activated protein kinases pathway. These finding suggest that HDAC inhibitors may provide an effective therapeutic strategy to selectively inhibiting the proliferation of TRAIL-resistant bladder cancer cells by enhancing TRAIL-mediated apoptosis.