Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several recent studies have suggested that the acquisition of the multidrug resistance (MDR) phenotype is associated with elevated invasion and metastasis of tumor cells. P-glycoprotein (P-gp), the major determinant in the generation of the MDR phenotype, was reported to be correlated with a more aggressive phenotype and poor prognosis in many forms of malignancies. However, a clear understanding of the association is still lacking. We previously showed that Anxa2, a calcium-dependent phospholipid-binding protein, interacts with P-gp and contributes to the invasiveness of MDR breast cancer cells. In the present study, a strong positive correlation between MDR1 and Anxa2 mRNA expression in invasive breast cancer tissues during cancer progression was observed. In addition, exposure to adriamycin significantly enhanced motility in breast cancer cells and increased levels of P-gp and Anxa2. Moreover, inhibition of P-gp activity, using selective P-gp modulators, was found to significantly inhibit the invasive capacity of MCF-7/ADR cells without affecting the interaction and co-localization between P-gp and Anxa2. However, suppression of P-gp pump activity and knockdown of MDR1 expression both disrupted adriamycin-induced Anxa2 phosphorylation. Interestingly, P-gp was further demonstrated to interact with Src, a tyrosine kinase upstream of Anxa2. Taken together, our results indicate that P-gp may promote the invasion of MDR breast cancer cells by modulating the tyrosine phosphorylation of Anxa2. The interaction between Anxa2 and P-gp is possibly, at least in part, responsible for the association between MDR and invasive potential in breast cancer cells.
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PMID:P-glycoprotein associates with Anxa2 and promotes invasion in multidrug resistant breast cancer cells. 2423 98

Blood-brain barrier dysfunction in epilepsy contributes to seizures and resistance to antiseizure drugs. Reports show that seizures increase brain glutamate levels, leading to barrier dysfunction. One component of barrier dysfunction is overexpression of the drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Based on our previous studies, we hypothesized that glutamate released during seizures activates cytosolic phospholipase A2 (cPLA2), resulting in P-gp and BCRP overexpression. We exposed isolated rat brain capillaries to glutamate ex vivo and used an in vivo-ex vivo approach of isolating brain capillaries from rats after status epilepticus (SE) and in chronic epileptic (CE) rats. Glutamate increased cPLA2, P-gp, and BCRP protein and activity levels in isolated brain capillaries. We confirmed the role of cPLA2 in the signaling pathway in brain capillaries from male and female mice lacking cPLA2. We also demonstrated, in vivo, that cPLA2 inhibition prevents overexpression of P-gp and BCRP at the blood-brain barrier in rats after status epilepticus and in CE rats. Our data support the hypothesis that glutamate signals cPLA2 activation, resulting in overexpression of blood-brain barrier P-gp and BCRP.-Hartz, A. M. S., Rempe, R. G., Soldner, E. L. B., Pekcec, A., Schlichtiger, J., Kryscio, R., Bauer, B. Cytosolic phospholipase A2 is a key regulator of blood-brain barrier function in epilepsy.
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PMID:Cytosolic phospholipase A2 is a key regulator of blood-brain barrier function in epilepsy. 3166 3