15d-PGJ2 induces apoptosis by reactive oxygen species-mediated inactivation of Akt in leukemia and colorectal cancer cells and shows in vivo antitumor activity.
OBJECTIVE
Recent studies have shown that 15-deoxy-Delta(12, 14)-prostaglandin J(2) (15d-PGJ(2)), a natural ligand for peroxisome proliferator-activated receptor-gamma (PPARgamma), inhibits cell proliferation and induces apoptosis. The specific molecular mechanisms underlying this effect remain to be elucidated. We examined whether 15d-PGJ(2) has antitumor activity in vitro and in vivo, and investigated the underlying mechanism.


METHODS
We examined 15d-PGJ(2)-induced apoptosis in human leukemia cells in the context of mitochondrial injury, oxidative damage, and signaling pathway disturbances. In addition, we investigated the antitumor effect of 15d-PGJ(2) in a mouse CT-26 s.c. tumor model and HL-60 leukemia xenograft model.


RESULTS
15d-PGJ(2) induced apoptosis in leukemia and colorectal cancer cells in a dose-dependent manner and led to generation of reactive oxygen species (ROS) through mitochondria and NADPH oxidase activation, activation of JNK, and inactivation of Akt, a serine/threonine-specific protein kinase. Constitutive activation of Akt for an engineered myristoylated protein prevented 15d-PGJ(2)-mediated apoptosis but not ROS generation. Collectively, these findings suggest a hierarchical model of apoptosis induced by 15d-PGJ(2) in human leukemia cells: oxidative injury represents a primary event resulting in Akt inactivation, which in turn leads to mitochondrial injury and apoptosis. Moreover, 15d-PGJ(2) markedly reduced growth of mouse CT-26 s.c. tumors and HL-60 xenograft tumors and down-regulated p-Akt and Akt expression in vivo.


CONCLUSIONS
These results suggest that Akt inactivation through ROS production may contribute to 15d-PGJ(2)-induced apoptosis in leukemia and colorectal cancer cell lines and that 15d-PGJ(2) may have therapeutic relevance in the treatment of human leukemia and colorectal cancer.
Shin
Sung-Won
SW
Department of Biochemistry, Dong-A University College of Medicine, Busan, South Korea.
Seo
Chi-Yeon
CY
Han
Hoon
H
Han
Jin-Yeong
JY
Jeong
Jin-Sook
JS
Kwak
Jong-Young
JY
Park
Joo-In
JI
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C477819:15-deoxyprostaglandin J2; D000970:Antineoplastic Agents; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D015230:Prostaglandin D2