Involvement of phosphatidylinositol-3-kinase in membrane ruffling induced by P-glycoprotein substrates in multidrug-resistant carcinoma cells

Biochemical Pharmacology
Jinming YangWilliam N Hait

Abstract

P-glycoprotein (P-gp) is a transmembrane protein that transports a variety of structurally and functionally diverse drugs. We recently found that the interaction of drugs with P-gp promoted invasion and metastasis. In this study, we sought to determine the mechanism by which the interaction of P-gp with its substrates leads to the earliest membrane changes associated with cellular invasion, i.e., membrane ruffling. We focused on the activation of phosphatidylinositol-3-kinase (PI-3-kinase), a lipid kinase that regulates actin cytoskeletal organization and cell movement. Sensitive or multidrug-resistant (MDR) MCF-7 (human breast cancer) or KB (human oral carcinoma) cells were treated with drugs or vehicle, and then were stained with phalloidin-tetramethyl-rhodamine isothiocyanate. Membrane ruffles were visualized using a fluorescence microscope. PI-3-kinase activity was determined by an in vitro immune-complex kinase assay and thin-layer chromatography. Drugs transported by P-gp, vinblastine and trans-flupenthixol, increased membrane ruffling and PI-3-kinase activity in the MDR cell lines, MCF-7/AdrR and KBV-1, which overexpress P-gp. This effect was not seen with mechlorethamine, a drug that is not transported by P-gp, and was ...Continue Reading

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Citations

Oct 19, 2007·The Journal of Investigative Dermatology·Marisa ColoneAgnese Molinari
Nov 14, 2012·The Journal of Pharmacy and Pharmacology·Can HuangYong Su
Aug 25, 2004·The Journal of Pharmacy and Pharmacology·M SawickaW Lewandowski
Apr 23, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Selina RaguzErnesto Yagüe
Apr 4, 2021·International Journal of Molecular Sciences·Ji HeYan Li

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