Intracellular pH and Multidrug Resistance Regulate Complement-mediated Cytotoxicity of Nucleated Human Cells

Weisburg, Jeffrey H.; Roepe, Paul D.; Dzekunov, Sergey; Scheinberg, David A.

doi:10.1074/jbc.274.16.10877

Cited by 53 publications

(36 citation statements)

References 36 publications

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“…In agreement with these studies were those of Bomstein and Fishelson (14), who demonstrated that P-gp ϩve tumor cell lines were more sensitive to complement-mediated lysis compared with matched P-gp Ϫve parental cells. However, in contrast to these findings were two reports demonstrating a role for functional P-gp in inhibiting membrane damage by complement (15,16). The authors of these studies presented evidence suggesting that P-gp-mediated intracellular alkalinization (pH i ) and/or decreased plasma membrane potential (V max ) resulted in a reduction in the rate of formation of the "membrane attack complex" (MAC) at the cell surface.…”

mentioning

confidence: 43%

“…Functional MACs consist of complement components C5b, C6, C7, C8, and multiple C9 molecules to form pores of ϳ100 Å (17). Expression of functional P-gp was shown to correlate with a reduction in the rate of MAC formation rather than the molecular stoichiometry of MAC complexes (16). It was hypothesized that altered pH i and/or V max may somehow directly or indirectly affect C9 polymerization, resulting in a net loss of functional MAC formation (16).…”

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confidence: 99%

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P-glycoprotein Does Not Protect Cells against Cytolysis Induced by Pore-forming Proteins

Johnstone

Tainton

Ruefli

et al. 2001

Journal of Biological Chemistry

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P-glycoprotein (P-gp) is an ATP-dependent drug pump that confers multidrug resistance (MDR). In addition to its ability to efflux toxins, P-gp can also inhibit apoptosis induced by a wide array of cell death stimuli that rely on activation of intracellular caspases for full function. We therefore hypothesized that P-gp may have additional functions in addition to its role in effluxing xenotoxins that could provide protection to tumor cells against a host response. There have been a number of contradictory reports concerning the role of P-gp in regulating complement activation. Given the disparate results obtained by different laboratories and our published results demonstrating that P-gp does not affect cell death induced by another membranolytic protein, perforin, we decided to assess the role of P-gp in regulating cell lysis induced by a number of different poreforming proteins. Testing a variety of different P-gpexpressing MDR cell lines produced following exposure of cells to chemotherapeutic agents or by retroviral gene transduction in the complete absence of any drug selection, we found no difference in sensitivity of P-gp ؉ve or P-gp ؊ve cells to the pore-forming proteins complement, perforin, or pneumolysin. Based on these results, we conclude that P-gp does not affect cell lysis induced by pore-forming proteins.P-glycoprotein (P-gp), 1 a member of the ATP-binding cassette (ABC) superfamily, is encoded by the MDR1 gene in humans and mdr1a and mdr1b in mice and has been demonstrated to act as a very efficient toxin efflux molecule (1, 2). In the clinical setting, expression of P-gp on tumor cells confers resistance to a wide range of different chemotherapeutic agents constituting a multidrug-resistant (MDR) phenotype and a poor prognosis. The current working model maintains that P-gp removes xenotoxins in an energy (ATP)-dependent manner by intercepting the drug as it moves through the lipid membrane and flips the drug from the inner leaflet to the outer leaflet and into the extracellular media (3). Consistent with its toxin clearance role, P-gp is expressed on the surface of normal human cells found in the gut, liver, and kidney tubules, and at blood-tissue barriers (4). However, P-gp is also expressed in the adrenal gland, hemopoietic stem cells, natural killer (NK) cells, antigen-presenting dendritic cells, and T and B lymphocytes (5, 6), and a role for P-gp in removing xenotoxins from these cells is not immediately apparent.Recent studies by our group and others have indicated that, in addition to its role as an efflux pump, P-gp also regulates programmed cell death mediated by some chemotherapeutic drugs, serum starvation, ultraviolet (UV) irradiation, and ligation of the cell surface death receptors Fas and tumor necrosis factor receptor (7-9). The ability of P-gp to inhibit cell death mediated by these diverse apoptotic stimuli appears to be due to P-gp-mediated inhibition of caspase activation. In contrast, other stimuli such as the chemotherapeutic agent hexamethylene bisacetamide (10), the prote...

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confidence: 43%

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confidence: 99%

P-glycoprotein Does Not Protect Cells against Cytolysis Induced by Pore-forming Proteins

Johnstone

Tainton

Ruefli

et al. 2001

Journal of Biological Chemistry

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“…[96][97][98][99] Recently, MDR1 has been demonstrated to regulate the apoptosis. [100][101][102][103][104][105][106][107][108] For example, Robinson et al reported that transfected MDR1 conferred resistance to apoptosis induced by serum starvation, which could be reversed by addition of verapamil. 104) However, little information is available concerning the role of MDR1 in the system.…”

Section: Mdr1 In Apoptosis and Immunologymentioning

confidence: 99%

“…107,108) Apoptosis is often preceded by intracellular acidification, 109,110) and MDR1 was suggested to delay the onset of the apoptosis via an increase of intracellular pH. 104) Some investigators pointed out that the change in intracellular pH contributed to the alteration of uptake by MDR1.…”

Section: Mdr1 In Apoptosis and Immunologymentioning

confidence: 99%

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Sakaeda

Nakamura

Okumura

2002

Biological & Pharmaceutical Bulletin

173

110

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The multidrug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily of membrane transporters. MDR1 acts as an energy-dependent efflux pump that exports its substrates out of cells. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multidrug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and detected 15 single nucleotide polymorphisms (SNPs). They also indicated that a polymorphism in exon 26 at position 3435 (C3435T), a silent mutation, affected the expression level of MDR1 protein in duodenum, and thereby the intestinal absorption of digoxin. To date, the genotype frequencies of C3435T have been investigated extensively using a larger population and interethnic difference has been elucidated, and a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on MDR1 genotype-related MDR1 expression and pharmacokinetics have also been performed around the world; however, results were not always consistent with Hoffmeyer's report. In this review, published reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping. In addition, recent investigations have raised the possibility that MDR1 and related transporters play a fundamental role in regulating apoptosis and immunology, and in fact, there are reports of MDR1-related susceptibility to inflammatory bowel disease, HIV infection and renal cell carcinoma. Herein, these issues are also summarized, and the current status of the knowledge in the area of pharmacogenomics of other transporters is briefly introduced.

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“…Further studies by several groups have suggested that MDR1 plays a role in apoptosis. For example, ectopic overexpression of MDR1 diminishes the apoptotic response induced by growth factor withdrawal (Robinson et al, 1997) decreases complement mediated cytotoxicity (Weisburg et al, 1999) and impairs the activation of caspase-dependent cell death pathways (Kojima et al, 1998;Smyth et al, 1998). In contrast, it is unknown if mdr1b overexpression a ects cell viability.…”

Section: Introductionmentioning

confidence: 99%

Mdr1b facilitates p53-mediated cell death and p53 is required for Mdr1b upregulation in vivo

et al. 2001

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The mdr1b gene is thought to be a``stress-responsive'' gene, however it is unknown if this gene is regulated by p53 in the whole animal. Moreover, it is unknown if overexpression of mdr1b a ects cell survival. The dependence of mdr1b upon p53 for upregulation was evaluated in p53 knockout mice. Wild-type (wt) or p537/7 mice were treated singly or in combination with gamma irradiation (IR) and/or the potent DNA damaging agent, diethylnitrosoamine (DEN). Both IR and DEN induced mdr1b in wild-type animals, but not in the p537/7 mice. IR also upregulated endogenous mdr1b in the H35 liver cell line, and the mdr1b promoter was activated by IR and activation correlated with p53 levels; moreover activation required an intact p53 binding site. Colony survival studies revealed that co-transfection of both mdr1b and p53 dramatically reduced colony numbers compared to cells transfected with either p53 or mdr1b alone and cells microinjected with both mdr1b and p53 had a more dramatic loss in viability compared to cells injected with either expression vector alone. Further studies using acridine orange and ethidium bromide to measure apoptosis revealed that mdr1b caused apoptosis and this was enhanced by p53, however the increased apoptosis required a functional p53 transactivation domain. These studies indicate that mdr1b is a downstream target of p53 in the whole animal and expression of mdr1b facilitates p53-mediated cell death. Oncogene (2001) 20, 303 ± 313.

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Intracellular pH and Multidrug Resistance Regulate Complement-mediated Cytotoxicity of Nucleated Human Cells

Cited by 53 publications

References 36 publications

P-glycoprotein Does Not Protect Cells against Cytolysis Induced by Pore-forming Proteins

P-glycoprotein Does Not Protect Cells against Cytolysis Induced by Pore-forming Proteins

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Mdr1b facilitates p53-mediated cell death and p53 is required for Mdr1b upregulation in vivo

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