TERMINAL DIFFERENTIATION OF HUMAN LIPOSARCOMA CELLS INDUCED BY LIGANDS FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AND THE RETINOID-X RECEPTOR

Induction of terminal differentiation represents a promising therapeut ic approach to certain human malignancies. The peroxisome proliferator -activated receptor gamma (PPAR gamma) and the retinoid X receptor alp ha (RXR alpha) form a heterodimeric complex that functions as a centra l regulator of adipocyte differentiation. Natural and synthetic ligand s for both receptors have been identified. We demonstrate here that PP AR gamma is expressed at high levels in each of the major histologic t ypes of human liposarcoma. Moreover, primary human liposarcoma cells c an be induced to undergo terminal differentiation by treatment with th e PPAR gamma ligand pioglita-zone, suggesting that the differentiation block in these cells can be overcome by maximal activation of the PPA R pathway, We further demonstrate that RXR-specific ligands are also p otent adipogenic agents in cells expressing the PPAR gamma/RXR alpha h eterodimer, and that simultaneous treatment of liposarcoma cells with both PPAR gamma- and RXR-specific ligands results in an additive stimu lation of differentiation. Liposarcoma cell differentiation is charact erized by accumulation of intracellular lipid, induction of adipocyte- specific genes, and withdrawl from the cell cycle. These results sugge st that PPAR gamma ligands such as thiazolidinediones and RXR-specific retinoids may be useful therapeutic agents for the treatment of lipos arcoma.