15-deoxyprostaglandin-j2 and Carcinoma--Non-Small-Cell-Lung

Cyclopentenone prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), which is generated from the dehydration of PGD(2), is a natural ligand of peroxisome proliferator-activated receptor gamma (PPARγ) and a potential apoptotic mediator. The synthetic PPARγ ligands, troglitazone and ciglitazone, inhibit tumor progression in many cells by PPARγ activation, but the mechanism of 15d-PGJ(2) is still unclear. In this study, GW9662, an antagonist of PPARγ, and quercetin, a natural antioxidant, were used to study the apoptotic mechanism of 15d-PGJ(2) in A549 cells. Results showed that 15d-PGJ(2) induced apoptosis, which was associated with the production of reactive oxygen species (ROS) and the decrease of GSH levels. Furthermore, quercetin reduced the activity of caspases in 15d-PGJ(2)-induced apoptotic processes. These results suggest that 15d-PGJ(2) induces apoptosis in A549 cells mainly through the formation of ROS; it does not depend on PPARγ activation. Moreover, these findings support the use of quercetin and PPARγ agonists in non-small cell lung carcinoma.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Caspases; Cell Line, Tumor; Glutathione; Humans; Lung Neoplasms; PPAR gamma; Prostaglandin D2; Quercetin; Reactive Oxygen Species; Thiazolidinediones

PGD2 (prostaglandin D2) is a mediator in various pathophysiological processes, including inflammation and tumorigenesis. PGD2 can be converted into active metabolites and is known to activate two distinct receptors, DP (PGD2 receptor) and CRTH2/DP2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). In the past, PGD2 was thought to be involved principally in the process of inflammation. However, in recent years, several studies have shown that PGD2 has anti-proliferative ability against tumorigenesis and can induce cellular apoptosis via activation of the caspase-dependent pathway in human colorectal cancer cells, leukaemia cells and eosinophils. In the lung, where PGD2 is highly released when sensitized mast cells are challenged with allergen, the mechanism of PGD2-induced apoptosis is unclear. In the present study, A549 cells, a type of NSCLC (non-small cell lung carcinoma), were treated with PGD2 under various conditions, including while blocking DP and CRTH2/DP2 with the selective antagonists BWA868C and ramatroban respectively. We report here that PGD2 induces A549 cell death through the intrinsic apoptotic pathway, although the process does not appear to involve either DP or CRTH2/DP2. Similar results were also found with H2199 cells, another type of NSCLC. We found that PGD2 metabolites induce apoptosis effectively and that 15d-PGJ2 (15-deoxy-Δ12,14-prostaglandin J2) is a likely candidate for the principal apoptotic inducer in PGD2-induced apoptosis in NSCLC A549 cells.

Topics: Apoptosis; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Chromatography, High Pressure Liquid; Cytochromes c; Cytosol; DNA Fragmentation; Humans; Hydantoins; Mitochondria; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Sulfonamides

To study the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in lung cancer cells, and to testify if the PPAR-gamma agonists can inhibit human lung cancer cell growth through induction of apoptosis, PPAR-gamma was detected in two lung cancer cell lines by RT-PCR and immunohistochemistry, the inhibition of human lung cancer cell growth was investigated by MTT and cell counts, and the apoptosis was assessed by TUNEL. The results showed that: (1) PPAR-gamma expressed on two lung cancer cell lines; (2) PPAR-gamma activated by ligands could inhibit human lung cancer cell growth remarkably; (3) PPAR-gamma agonists could induce apoptosis to inhibit lung cancer cell growth. It was concluded that PPAR-gamma expressed in lung cancer cell can be activated by ligands and can inhibit lung cancer cell growth through induction of apoptosis.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Division; Gene Expression Regulation, Neoplastic; Humans; Ligands; Lung Neoplasms; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Tumor Cells, Cultured