Cell-cycle-dependent turnover of P-glycoprotein in multidrug-resistant cells

Regulation of P-glycoprotein (Pgp) expression occurs not only at the DNA and mRNA level but also at the protein level. We showed previously that Pgp was stabilized when multidrug-resistant CH(R)C5 and SKVCR 2.0 ovarian cell lines were subjected to serum-starved or high-cell-density growth conditions, whereas Pgp turnover in a leukemic multidrug-resistant cell line, CEMVLB0.1, was not affected by serum starvation (Muller et al., 1995). On further analysis, we have observed that the majority of the CH(R)C5 and SKVCR 2.0 cells under these conditions were in the G1/G0 phase of the cell cycle, whereas the cell cycle of CEMVLB0.1 cells was not affected. Pgp in CEMVLB0.1 cells was stabilized only when the cell cycle was delayed in the G1/G0 phase by using amino acid-deficient growth medium. In CH(R)C5 cells, Pgp half-life was also considerably increased when the cell cycle of these ovary-derived cells was delayed in the G1/G0 phase by using high concentrations of progesterone under normal serum growth conditions. In contrast, Pgp stability was not greatly affected if these cells were delayed in the S or G2/M phase of the cell cycle with Ara-C, cisplatin, or colchicine under the same conditions. Insulin-like growth factors could release the serum-starved CH(R)C5 and SKVCR2.0 cells from the G1/G0 phase and destabilized Pgp. These results indicate that Pgp turnover is a cell-cycle-related process in MDR cells.