Mutational analysis of P-glycoprotein: suppression of caspase activation in the absence of ATP-dependent drug efflux

Tainton, Kellie M.; Smyth, Mark J.; Jackson, Jacob T.; Tanner, Jane E.; Cerruti, Loretta; Jane, Stephen M.; Darcy, Phillip K.; Johnstone, Ricky W.

doi:10.1038/sj.cdd.4401440

Cited by 92 publications

(62 citation statements)

References 44 publications

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“…In fact, this antiapoptotic effect persisted even when MDR1/Pgp was rendered inactive by mutation of key lysine residues of the Walker A region. Intriguingly, these data suggest a dual activity model for MDR1/Pgp-induced MDR, involving both ATPase-dependent drug efflux and ATPase-independent inhibition of apoptosis (369). Although direct interaction between MDR1/Pgp and apoptotic enzymes has not been documented, it has also been hypothesized that MDR1/ Pgp acts as a primary antiapoptotic regulator by reducing ceramide levels either through the reduction of inner leaflet sphingomyelin pools or through the modulation of the glyco-sphingomyelin pathway (222,377).…”

Section: Physiological and Pharmacological Functions Of Mdr1/pgpmentioning

confidence: 97%

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Sarkadi¹,

Homolya²,

Szakács³

et al. 2006

Physiological Reviews

642

532

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In this review we give an overview of the physiological functions of a group of ATP binding cassette (ABC) transporter proteins, which were discovered, and still referred to, as multidrug resistance (MDR) transporters. Although they indeed play an important role in cancer drug resistance, their major physiological function is to provide general protection against hydrophobic xenobiotics. With a highly conserved structure, membrane topology, and mechanism of action, these essential transporters are preserved throughout all living systems, from bacteria to human. We describe the general structural and mechanistic features of the human MDR-ABC transporters and introduce some of the basic methods that can be applied for the analysis of their expression, function, regulation, and modulation. We treat in detail the biochemistry, cell biology, and physiology of the ABCB1 (MDR1/P-glycoprotein) and the ABCG2 (MXR/BCRP) proteins and describe emerging information related to additional ABCB- and ABCG-type transporters with a potential role in drug and xenobiotic resistance. Throughout this review we demonstrate and emphasize the general network characteristics of the MDR-ABC transporters, functioning at the cellular and physiological tissue barriers. In addition, we suggest that multidrug transporters are essential parts of an innate defense system, the “chemoimmunity” network, which has a number of features reminiscent of classical immunology.

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Section: Physiological and Pharmacological Functions Of Mdr1/pgpmentioning

confidence: 97%

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Sarkadi¹,

Homolya²,

Szakács³

et al. 2006

Physiological Reviews

642

532

View full text Add to dashboard Cite

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“…In addition to this generally accepted role as a drug transporter, P-gp seems to be active as a regulatory protein with antiapoptotic effects, and this additional role is independent of its transport function (Pallis and Russell 2000;Ruefli 2003;Breier et al 2013). The main evidence for this assumption is the fact that a transport-defective P-gp mutant expressed in CEM lymphoma cells decreases apoptosis progression induced by vincristine (VCR) (Tainton et al 2004). Moreover, we have described less pronounced apoptosis progression induced by cisplatin (cisPt, not a P-gp substrate) in two P-gp-positive mouse leukemia cell variants, obtained either by selection with VCR (L1210/R) or by transfection with the human gene encoding P-gp (L1210/T) when compared with P-gp-negative parental L1210 cells (Gibalova et al , 2012.…”

Section: Introductionmentioning

confidence: 97%

The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

Pavlíková

Šereš²,

Imrichova³

et al. 2016

gpb

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Abstract. In P-gp-positive cell variants obtained from L1210 cells either by selection with vincristine (L1210/R) or by transfection with the human gene encoding P-gp (L1210/T), we have previously described cross-resistance to tunicamycin (TNM), a protein N-glycosylation inhibitor. Here we studied whether this cross-resistance also underlies P-gp-positive variants of human acute myeloid leukemia cells (AML) derived from SKM-1 and MOLM-13 cells (SKM-1/VCR, SKM-1/LEN, MOLM-13/ VCR) by selection with vincristine (VCR) and lenalidomide (LEN). While SKM-1/LEN cells were P-gp positive, no P-gp was detected in MOLM-13/LEN cells. P-gp-positive cells could be repeatedly passaged in medium containing TNM. In contrast, more than 90% of P-gp-negative cells were entering and progressing through cell death mechanisms after the third passage in medium containing TNM. Combined apoptosis/necrosis cell death was detected in L1210 cells after exposure to TNM. Passaging of P-gp-negative AML cells in medium containing TNM induced preferentially apoptosis. Damage to P-gp-negative cells induced with TNM was associated with arrest in the G1 phase of the cell cycle. P-gp-positive leukemia cells differed from P-gp-negative cells in the composition of plasma membrane glycoproteins, which we monitored with the aid of different lectins. The application of TNM to cells induced additional changes in membrane-linked glycosides.

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“…In addition to being a drug-efflux pump, Pgp has been shown to confer resistance to apoptosis induced by many chemotherapeutic drugs. It will be interesting to determine whether the inhibitory effect of Pgp on caspase activation [10], which does not require ATP hydrolysis activity [11], can be transferred to acceptor cells. The observed slower growth of acceptor cells following transfer of Pgp suggests the involvement of additional proteins or factors.…”

Section: Intercellular Transfer Of Pgpmentioning

confidence: 99%

A novel way to spread drug resistance in tumor cells: functional intercellular transfer of P-glycoprotein (ABCB1)

Ambudkar

Sauna

Gottesman

et al. 2005

Trends in Pharmacological Sciences

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Intercellular transfer of proteins is a mode of communication between cells that is crucial for certain physiological processes. Chemotherapy is the treatment of choice for ~50% of all cancers. However, multidrug resistance mediated by drug-efflux pumps such as P-glycoprotein (Pgp) minimizes the effectiveness of such therapy in a large number of patients. A new study demonstrates the functional intercellular transfer of Pgp. Non-genetic transfer of the multidrug resistance phenotype raises fascinating questions about the mechanism and regulation of cell-surface membrane-proteinmediated spread of traits. Transfer of membrane proteins between cellsBiologists have studied the role of diffusible molecules in communication between cells for almost a century. More recently, the clustering of distinct ligands or receptors at the tips of specific cellular extensions has been shown to offer a sophisticated and efficient communication network. However, several recent studies suggest that the wholesale transfer of membrane proteins might be commonplace in biology. Intercellular transfer of membrane proteins [1] has been shown to be an integral part of neuronal and immunological synapses, signals for organogenesis and tumor metastasis [2] and the spreading of the glycosylphosphatidylinositol (GPI)-anchored prion PrP c [3] (Figure 1). The immunological synapse, where the exchange of membrane proteins is rampant [1], is being recognized increasingly as central to immune cell communication. For example, antigen-presenting dendritic cells secrete vesicles called exosomes that carry major histocompatibility complex (MHC) proteins to T cells via a pathway that is under the control of cytokines and chemokines [4]. Similarly, the chemokine receptor CCR5 is released from the peripheral blood mononuclear cells in microparticles (0.1-2.0 μm), resulting in the transfer of CCR5 to CCR5-negative cells [5]. CCR5 is the principal coreceptor for the HIV-1 virus and thus such transfer of a receptor is of considerable concern. Finally, convincing evidence has been provided for the functional role of 'tunneling nanotubes' in complex networks [6] through which a significant exchange of membrane components occurs between a variety of cells (e.g. 721.221 B, rat PC12 and HEK293T cells). Multidrug resistance and P-glycoproteinClassical multidrug resistance is attributed to the elevated expression of ATP-dependent drugefflux pumps ABCB1 [also known as P-glycoprotein (Pgp)], ABCC1 [also known as multidrug resistance-associated protein (MRP1)] and ABCG2 [also known as breast cancer-resistance protein (BCRP) and mitoxantrone-resistance protein (MXR)], all of which belong to the superfamily of ATP-binding cassette (ABC) transporters [7]. Efflux mediated by ABC drug

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Mutational analysis of P-glycoprotein: suppression of caspase activation in the absence of ATP-dependent drug efflux

Cited by 92 publications

References 44 publications

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

A novel way to spread drug resistance in tumor cells: functional intercellular transfer of P-glycoprotein (ABCB1)

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