15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) sensitizes human leukemic HL-60 cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through Akt downregulation
15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) sensitizes human leukemic HL-60 cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through Akt downregulation
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DOI：
10.1007/s10495-007-0124-2
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发表时间：
2007-11-01
期刊：
影响因子：
7.2
通讯作者：
Park, Joo-In
中科院分区：
文献类型：
--
作者：
Han, Hoon;Shin, Sung-Won;Park, Joo-In
虽然肿瘤坏死因子 (TNF) 相关凋亡诱导配体 (TRAIL) 是一种有前景的癌症治疗新药，但对 TRAIL 的耐药性仍然是治疗挑战。鉴定与 TRAIL 联合使用以增强白血病细胞凋亡的药物将增加该药物作为白血病治疗的潜在效用。在这里，我们发现 15-脱氧-Delta(12,14)-前列腺素 J(2) (15d-PGJ(2)) 是过氧化物酶体增殖物激活受体 γ (PPAR γ) 的天然配体，可以使 TRAIL 耐药性白血病 HL-60 细胞对 TRAIL 诱导的细胞凋亡敏感。 15d-PGJ(2) 对 TRAIL 诱导的细胞凋亡的敏感性未被 PPAR gamma 抑制剂 (GW9662) 阻断，表明 PPAR gamma 不依赖的机制。该过程伴随着 caspase-8、caspase-9 和 caspase-3 的激活，并伴随 Bid 和 PARP 裂解。我们观察到与 15d-PGJ(2) 和 TRAIL 共同治疗后 XIAP、Bcl-2 和 c-FLIP 显着降低。我们还观察到 15d-PGJ(2) 和 TRAIL 共同处理对 Akt 表达和磷酸化的抑制。此外，Akt 抑制剂 IV 使 Akt 失活使人白血病 HL-60 细胞对 TRAIL 敏感，表明 Akt 抑制在这些事件中发挥着关键作用。总之，这些发现表明 15d-PGJ(2) 可能通过下调 Akt 的表达和磷酸化来增强 TRAIL 诱导的人白血病细胞凋亡。
While tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising new agent for the treatment of cancer, resistance to TRAIL remains a therapeutic challenge. Identifying agents to use in combination with TRAIL to enhance apoptosis in leukemia cells would increase the potential utility of this agent as a therapy for leukemia. Here, we show that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a natural ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma), can sensitize TRAIL-resistant leukemic HL-60 cells to TRAIL-induced apoptosis. The sensitization to TRAIL-induced apoptosis by 15d-PGJ(2) was not blocked by a PPAR gamma inhibitor (GW9662), suggesting a PPAR gamma-independent mechanism. This process was accompanied by activation of caspase-8, caspase-9, and caspase-3 and was concomitant with Bid and PARP cleavage. We observed significant decreases in XIAP, Bcl-2, and c-FLIP after cotreatment with 15d-PGJ(2) and TRAIL. We also observed the inhibition of Akt expression and phosphorylation by cotreatment with 15d-PGJ(2) and TRAIL. Furthermore, inactivation of Akt by Akt inhibitor IV sensitized human leukemic HL-60 cells to TRAIL, indicating a key role for Akt inhibition in these events. Taken together, these findings indicate that 15d-PGJ(2) may augment TRAIL-induced apoptosis in human leukemia cells by down-regulating the expression and phosphorylation of Akt.