Regulation of the function of P-glycoprotein by epidermal growth factor through phospholipase C

Jin-Ming Yang, Gregory F. Sullivan, William N. Hiat

Research output: Contribution to journalArticle

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Abstract

Many multidrug-resistant (MDR) cell lines overexpress the epidermal growth factor receptor (EGFR) as well as P-glycoprotein (P-gp). However, the role of the increased EGFR in P-gp-mediated drug resistance remains unclear. Since recent studies suggest that activation of phospholipase C (PLC) could increase the phosphorylation of P-gp, and activation of the EGFR would also activate PLC, we investigated whether the effect of epidermal growth factor (EGF) on the phosphorylation of P-gp was mediated through PLC. Treatment of the human MDR breast cancer cell line, MCF-7/AdrR with EGF increased the phosphorylation of P-gp by 20-50%. The increased phosphorylation of P-gp was accompanied by stimulation of PLC activity, as measured by the production of inositol, 1,4,5-trisphosphate and diacylglycerol, products of phosphatidylinositol-4,5 bisphosphate hydrolysis. Treatment of MDR cells with EGF also had detectable effects on P-gp function. For example, following incubation of MCF-7 AdrR cells with EGF, we observed a consistent decrease in total vinblastine (VBL) accumulation. Kinetic analysis revealed this change to be due to an increase in membrane efflux. The latter was measured by the initial uptake velocity which was inhibited by EGF. VBL uptake measured at 0- 320 sec was inhibited by 20-40%, which was associated with a similar increase in VBL efflux. EGF had no effect on drug accumulation, uptake, or efflux in sensitive MCF-7 cells. These data indicate that EGF can modulate the phosphorylation and function of P-gp, and suggest that this effect may be initiated by the activation of PLC.

Original languageEnglish (US)
Pages (from-to)1597-1604
Number of pages8
JournalBiochemical Pharmacology
Volume53
Issue number11
DOIs
StatePublished - Jun 1 1997

Fingerprint

P-Glycoprotein
Type C Phospholipases
Epidermal Growth Factor
Phosphorylation
Vinblastine
Epidermal Growth Factor Receptor
Chemical activation
MCF-7 Cells
Cells
Cell Line
Inositol 1,4,5-Trisphosphate
Diglycerides
Phosphatidylinositols
Drug Resistance
Pharmaceutical Preparations
Hydrolysis
Breast Neoplasms
Membranes
Kinetics

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

Yang, Jin-Ming ; Sullivan, Gregory F. ; Hiat, William N. / Regulation of the function of P-glycoprotein by epidermal growth factor through phospholipase C. In: Biochemical Pharmacology. 1997 ; Vol. 53, No. 11. pp. 1597-1604.
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Regulation of the function of P-glycoprotein by epidermal growth factor through phospholipase C. / Yang, Jin-Ming; Sullivan, Gregory F.; Hiat, William N.

In: Biochemical Pharmacology, Vol. 53, No. 11, 01.06.1997, p. 1597-1604.

Research output: Contribution to journalArticle

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