Abstract
Studies have demonstrated that manumycin, a farnesyltransferase inhibitor, enhances the cytotoxic effect of paclitaxel in anaplastic thyroid cancer cells and in xenografts, but the mechanism of this effect is unknown. Parathyroid hormone-related protein (PTHrP) may function as an oncoprotein that inhibits apoptosis and enhances cell proliferation, in addition to its role as the mediator of humoral hypercalcemia of malignancy. We hypothesized that this protein might have a novel role in anaplastic thyroid cancer. Five anaplastic thyroid cancer cell lines (ARO, DRO, KAT-4, Hth-74, C-643) were examined for PTHrP expression in vitro by immunohistochemistry (IHC), radioimmunoassay, and Western blot (IP/WB) analyses. PTHrP expression was also examined in an in vivo xenograft model. The effects of manumycin and paclitaxel on PTHrP expression were studied. All 5 ATC cell lines were found to robustly express PTHrP by IHC of fixed cells and radioimmunoassay of cell lysates and conditioned culture media (range, 468 +/- 55 to 1410 +/- 195 pg/mg cellular protein). Manumycin (54 micromol/L), but not paclitaxel (22 micromol/L), decreased the amount of PTHrP. Further, PTHrP was decreased in KAT-4 xenografts in nude mice that had been treated for 3 weeks with biweekly intraperitoneal injections of manumycin (7.5 mg/kg), compared with control mice by IHC. On Western blot analyses, fractionation of radiolabeled proteins showed that manumycin decreased synthesis of PTHrP in cytoplasm, with the amount of newly synthesized PTHrP in the nucleus and increased ubiquitination of PTHrP suggesting increased degradation of PTHrP through the proteasome pathway. Manumycin inhibits cell proliferation and decreases PTHrP levels in anaplastic thyroid cancer cells in vitro and in vivo and decreases the PTHrP level in the nucleus where PTHrP may function as an oncoprotein. These data suggest that PTHrP has a novel role in anaplastic thyroid cancer and that modulation of PTHrP levels may be of therapeutic benefit in this lethal malignancy.
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