PPARgamma ligand 15-deoxy-delta 12,14-prostaglandin J2 sensitizes human colon carcinoma cells to TWEAK-induced apoptosis.
BACKGROUND
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been shown to induce colon cancer cell apoptosis in the presence of interferon-gamma. We hypothesized that co-treatment using TWEAK with other pro-apoptosis agents could sensitize death receptor-resistant colon cancer cells.


METHODS
The effects of chemopreventive agents and TWEAK on cell death and apoptosis were determined using propidium iodide (PI) exclusion and M30 CytoDEATH.


RESULTS
We found that 15d-PGJ(2) sensitizes colon cancer cells to TWEAK-induced apoptosis. Caspase inhibition reduced 15d-PGJ(2)-, but not 15d-PGJ(2)+TWEAK-induced apoptosis. 15d-PGJ(2) promoted reactive oxygen species (ROS) production and dissipation of mitochondrial potential (DeltaPsi(m)) that were more marked with combined treatment. ROS, DeltaPsi(m) and cell death were partially normalized by the antioxidant N-acetylcysteine. TWEAK induced nuclear factor-kappa B activation, which was attenuated by 15d-PGJ(2). 15d-PGJ(2) reduced the expression of the anti-apoptotic proteins BCL-X(L) and MCL-1, while increasing BAX and translocation of cytochrome c and apoptosis-inducing factor.


CONCLUSIONS
15d-PGJ(2) sensitized cancer cells to TWEAK-induced apoptosis through an ROS-dependent cell death pathway and may have chemotherapeutic utility as an apoptosis-enhancing agent.
FRCPC FACG, McGill Center for IBD Research, C10.145, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada.
Serge
S
Dionne
Emile
E
Levy
Denise
D
Levesque
Ernest G
EG
Seidman
D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000074049:Cytokine TWEAK; D004357:Drug Synergism; D019073:HT29 Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008024:Ligands; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000494:pharmacology*
C530721:(N-(9-fluorenylmethoxycarbonyl)-)-L-leucine; C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002087:Butyrates; D000074049:Cytokine TWEAK; D008024:Ligands; D047495:PPAR gamma; C109743:TNFSF12 protein, human; D045162:Thiazolidinediones; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma; D007930:Leucine; D015230:Prostaglandin D2; C039671:ciglitazone