MEVALONATE CONTROLS CYTOSKELETON ORGANIZATION AND CELL MORPHOLOGY IN THYROID EPITHELIAL-CELLS

Blockade of mevalonate synthesis by the 3-hydroxy-3-methylglutaryl Coe nzyme A reductase inhibitor mevinolin (lovastatin) causes FRTL-5 thyro id cells to undergo significant morphological changes; these include a transition from a flat, polygonal to a round shape, the development o f cytoplasmic arborizations, and the loss of contact between neighbori ng cells. Immunofluorescence studies of cytoskeletal structures show t hat, at early times after administering the drug, and before the round phenotype develops, stress fibers disassemble while the peripheral ac tin filaments, which are adjacent to the cytoplasmic face of the plasm a membrane, appear largely unaffected. Subsequently, when this cortica l actin network becomes fragmented, cells start to round up and become separated from neighbors. Microtubules become disconnected from the p lasma membrane and retract toward the cell center, although they do no t appear depolymerized; indeed, at this stage, cytoplasmic elongations contain mostly intact microtubules. After exposure to mevinolin FRTL- 5 cells also lose vinculin-related substrate contacts. Treatment of ce lls with either cycloheximide or colchicine abolishes morphological ch anges induced by mevinolin, suggesting that ongoing protein synthesis and microtubule integrity are prerequisites for the drug to be effecti ve. Both cytoskeletal and morphological perturbations can be reversed by mevalonate, but not by cholesterol or the non-sterol derivatives of mevalonate such as dolichol, ubiquinone, and isopentenyladenine, indi vidually or in combination. It is suggested that mevalonate deficiency may impair formation of isoprenylated proteins important for cytoskel etal organization and stability.