Folate receptor function is regulated in response to different cellular growth rates in cultured mammalian cells

The folate receptor (FR) binds physiologic folates with nmol/L affinities a nd is expected to play an important role in transporting serum folates into cells that express this receptor. Although it has been shown that FR expre ssion increases when extracellular levels of folate are low, whether this r eceptor is regulated in response to altered cellular requirements for folat es or by intracellular levels of this vitamin has not been investigated. In this study, FIR levels, FR function and cellular folate levels were measur ed in cells with different growth rates to investigate FR regulation of thi s receptor under conditions in which cellular requirements for folate are a ltered. These experiments used cells that endogenously express FR (JAR, Cac o-2 and MA-104) and cells stably transfected with this receptor (FRGPI-16 a nd FRTM-8). FR function decreased as cellular growth slowed in four of the five cell lines examined. Although cellular folate levels also decreased as cells reached confluence, the total amount of cellular folate in the cultu re remained constant, suggesting the depleted cellular folate was because o f the cell partitioning its pool throughout cell division, not because of d ecreased FR function. Conversely, there was an inverse association with FR levels and cell growth (r = -0.998 to -0.999, P < 0.05) in cells endogenous ly expressing FR, with a significant increase in the percentage of total FR located in an intracellular compartment as growth slowed. These results su ggest FR function is regulated by cellular requirements for folates but not in response to changing FR levels or cellular levels of this vitamin.