This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our in vitro studies comparing the two most common isomers of CLA (t10,c12 and c9,t11-CLA) show that both possess anti-proliferative activities, however only t10,c12-CLA induced caspase related apoptosis in human colon cancer HCA-7 cells. Treatment with either isomer of CLA reduced basal levels of prostaglandin E2 (PGE2) while increasing cycloxygenease-2 (COX-2) protein expression an affect that was greatest with t10, c12-CLA. Treatment with t10, c12-CLA was also capable of reducing the phosphorylation of Erk1/2 when compared to both c9, t11-CLA and linoleic acid treated cells. PGE2 feedback experiments demonstrate that t10,c12-CLA induces caspase 3/7 activity and reduces Erk1/2 activation in the presence of PGE2 suggesting that the activity of CLA may have PGE2 independent components. Further, t10,c12-CLA treatment was found to increased the detection of the endogenous PPAR-? ligand 15-deoxy-?12,14 prostaglandin J2 (15d-PGJ2) along with nuclear localization of PPAR?, and PPAR transactivational activity. The immediate synthesis of 15d-PGJ2 was inhibited by pretreatment with the COX-2 specific inhibitor NS-398 suggesting that COX-2 is partially responsible for the production of 15d-PGJ2. Treating cells with the PPAR? antagonist GW9662 partially inhibited t10,c12 CLA associated caspase 3/7 activity illustrating both PPAR independent and dependent components to the activity of t10,c12-CLA. Based on these observations, CLA may exert some of its anti-tumorigenic effects in part through 1) elevating 15d-PGJ2 levels 2) inhibiting Erk1/2 phosphorylation/activation and 3) altering PPAR? signaling in colon cancer cells. Dr. Muga has graduated as COBRE PI, so that this subproject will not be included in the next year of funding.
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