Follicular thyroid cancer cell growth inhibition by proteosome inhibitor MG132.
BACKGROUND
Effective therapies for the subset of follicular thyroid cancer (FTC) patients with aggressive, metastatic disease are lacking. Therefore, we sought to determine the effects of proteosome inhibition, an emerging class of chemotherapeutic agents, on metastatic FTC cells.


METHODS
Human metastatic FTC cells (FTC236) were treated in vitro with the proteosome inhibitor MG132 (0 to 800 nM). Western blot analysis was performed on whole cell lysates isolated after 2 d. To measure cell growth, we performed an MTT cellular proliferation assay over 6 d.


RESULTS
Treatment of FTC236 cells with MG132 led to dose-dependent cell growth inhibition. Increases in inactive, phosphorylated GSK-3beta, and active beta-catenin also were observed. With 800 nM MG132, growth was reduced by 87% at 6 d (P < 0.0001). This reduction in cellular proliferation correlated with the degree of GSK-3beta inhibition. MG132 treatment also caused increased p21(Waf1/Cip1) and decreased cyclin D1 expression, suggesting that growth suppression may occur through cell cycle arrest.


CONCLUSIONS
Growth of metastatic human FTC cells appears to be suppressed by proteosome inhibition. Whether this effect is directly due to cell cycle arrest and inactivation of GSK-3beta signaling is unclear. Nonetheless, these compounds may become novel treatments for aggressive, metastatic FTC.
Stoll
Samantha J
SJ
Endocrine Surgery Research Laboratory, Department of Surgery, University of Wisconsin, Madison, WI 53792-3284, USA.
Pitt
Susan C
SC
Chen
Herbert
H
D018263:Adenocarcinoma, Follicular / Q000188:drug therapy* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation; D061988:Proteasome Inhibitors; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D007976:Leupeptins; D061988:Proteasome Inhibitors; D051176:beta Catenin; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D054462:p21-Activated Kinases; D038362:Glycogen Synthase Kinase 3; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde