15-Deoxy-delta 12,14-prostaglandin J2 (15d-PGJ 2) sensitizes human leukemic HL-60 cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through Akt downregulation.
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 J2 (15d-PGJ2), a natural ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), can sensitize TRAIL-resistant leukemic HL-60 cells to TRAIL-induced apoptosis. The sensitization to TRAIL-induced apoptosis by 15d-PGJ2 was not blocked by a PPARgamma inhibitor (GW9662), suggesting a PPARgamma-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-PGJ2 and TRAIL. We also observed the inhibition of Akt expression and phosphorylation by cotreatment with 15d-PGJ2 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-PGJ2 may augment TRAIL-induced apoptosis in human leukemia cells by down-regulating the expression and phosphorylation of Akt.
Han
Hoon
H
Department of Biochemistry, Dong-A University College of Medicine, 3 Ga 1, Dongdaesin-Dong, Seo-Gu, Busan 602-714, South Korea.
Shin
Sung-Won
SW
Seo
Chi-Yeon
CY
Kwon
Hyuk-Chan
HC
Han
Jin-Yeong
JY
Kim
In-Hoo
IH
Kwak
Jong-Young
JY
Park
Joo-In
JI
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology*; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*