The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis

Smyth, Mark J.; Krasovskis, Erika; Sutton, Vivien R.; Johnstone, Ricky W.

doi:10.1073/pnas.95.12.7024

Cited by 335 publications

(249 citation statements)

References 48 publications

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“…CEM GFP ± P-gp WT , CEM GFP -P-gp MUT , and CEM GFP cells were labeled with 51 Cr and then cultured with APO-1-1 anti-Fas antibody and cross-linked with protein A for 0 ± 6 h. CEM GFP ± P-gp MUT , and CEM GFP cells displayed significant cell death after 6 h incubation with APO-1-1 ( Figure 2A). By contrast and consistent with our previous studies using drug-selected P-gp expressing cells, 9 cell death induced by Fas antibodies in CEM GFP ± P-gp WT cells was significantly attenuated over both a dose and time range of APO-1-1 (Figure 2A, B). Taken together, these results suggested that Pgp ATPase and/or efflux function was necessary to confer resistance to Fas-induced cell death.…”

Section: Resultscontrasting

confidence: 52%

P-glycoprotein inhibits caspase-8 activation but not formation of the death inducing signal complex (disc) following Fas ligation

et al. 2002

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Previous studies by our laboratory have shown that the drug transporter protein P-glycoprotein, P-gp, can specifically inhibit Fas-induced caspase-3 activation and apoptosis. Importantly, inhibition of both caspase-3 activation and cell death could be reversed by pharmacological and antibody inhibitors of P-gp function. However, the molecular mechanisms underpinning P-gp-mediated resistance to Fas-induced cell death and caspase activation remained unknown. We therefore sought to identify the point(s) within the death receptor pathway at which P-gp exerted its inhibitory effect and to determine whether the ATPase activity of P-gp was required. Structure-function analysis determined that ATP hydrolysis was necessary for P-gp to confer resistance to Fasinduced caspase activation and cell death. Importantly, although both FADD and caspase-8 were recruited to the Death Inducing Signal Complex (DISC) in wild-type P-gp expressing cells following Fas ligation, subsequent activation of caspase-8 at the DISC was inhibited. The ability of P-gp to inhibit caspase-8 activation was also ATP dependent. These studies demonstrate that P-gp inhibits Fas-induced caspase-8 activation but not formation of the DISC and that this activity of P-gp is dependent on ATP hydrolysis.

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Section: Resultscontrasting

confidence: 52%

P-glycoprotein inhibits caspase-8 activation but not formation of the death inducing signal complex (disc) following Fas ligation

et al. 2002

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“…31 Therefore, in addition to drug transport function, P-gp may confer cell resistance by regulating some caspase-dependent apoptotic pathways. 32 Moreover, recent studies substantiated that soluble factors (cytokines, hormones, growth factors) or cell interaction with extracellular matrix (ECM) present in the tumor's microenvironment are determining factors in cancer cell survival and the emergence of drug resistance. 33,34 In particular, the BM microenvironment is likely to promote tumor cell survival by conferring protection from cytotoxic drugs.…”

Section: Discussionmentioning

confidence: 99%

MYCN Enhances P-gp/MDR1 Gene Expression in the Human Metastatic Neuroblastoma IGR-N-91 Model

Blanc

Goldschneider

Ferrandis

et al. 2003

The American Journal of Pathology

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Despite intensive high-dose chemotherapy and autologous hematopoietic stem cell transplantation, disseminated neuroblastoma (NB) frequently proves to be chemosensitive but not chemocurable, and more often so in NB-presenting MYCN amplification. To assess the direct relationship between the MYCN oncogene and chemoresistance acquisition during NB metastatic dissemination, we have studied MYCN and MDR1 genes using the human IGR-N-91 ectopic xenograft metastatic model. This characterized experimental in vitro model includes human neuroblasts derived from a subcutaneous primary tumor xenograft, disseminated blood cells, myocardium, and bone marrow (BM) metastatic cells. All IGR-N-91-derived neuroblasts harbor a consistent MYCN genomic content but, unlike primary tumor xenograft, BM, and myocardium, human neuroblasts elicit a concomitant increase in MYCN and MDR1 transcripts levels, consistent with chemoresistance phenotype and active P-gp. In contrast, no variation of MRP1 transcript level was associated with the metastatic process in this model. Using an MDR1 promoter-CAT construct, we have shown that the MycN protein activates MDR1 transcription both in exogenous transient MYCN- Neuroblastoma (NB), the most common solid tumor of early childhood, originating in tissues of the sympathetic nervous system, presents extreme heterogeneity clinically, histologically, and genetically. From a clinical point of view, NBs are classified according to stage (localized stages 1, 2, and 3, and metastatic stage 4) and the child's age at diagnosis (Ͻ1 year and Ͼ1 year). On presentation, stage-4 NBs systematically present involved bone marrow (BM). From a biological point of view, following cytogenetic and genetic research throughout the past 2 decades, NB tumors can be classified into three types depending on genomic and genetic alterations.

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“…Multidrug resistance (MDR) is a fatal event encountered during cancer chemotherapy (Chen et al, 1986;Gros et al, 1986a, b;Cole et al, 1992;Robinson et al, 1997;Smyth et al, 1998;Johnstone et al, 1999). To understand better MDR development, we employed the methylation sensitive-representational difference analysis technique (Yuan et al, 1999;Shan et al, 2000Shan et al, , 2002a to study DNA hypermethylation events in a human MDR breast cancer cell line, MCF7/AdrR, as compared to its parental line, MCF7/WT.…”

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confidence: 99%

WTH3 is a direct target of the p53 protein

Tian

Wang

2007

Br J Cancer

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Previous results showed that overexpression of the WTH3 gene in multidrug resistance (MDR) cells reduced MDR1 gene expression and converted their resistance to sensitivity to various anticancer drugs. The WTH3 gene promoter was found to be differentially regulated in paired MDR vs non-MDR MCF7 cells owing to epigenetic modifications and transcription factor modulations. To understand further the mechanisms that govern WTH3's differential expression, we uncovered a p53-binding site in its promoter, which indicated that WTH3 could be regulated by the p53 gene. This hypothesis was then tested by different strategies. The resulting data revealed that (1) the WTH3 promoter was upregulated by the p53 transgene in diverse host cells; (2) there was a correlation between WTH3 expression levels and p53 gene status in a cell line panel; (3) a WTH3 promoter region was directly targeted by the p53 protein in vitro and in vivo. In addition, overexpression of the WTH3 gene promoted the apoptotic phenotype in host cells. On the basis of these findings, we believe that the negative role played by the WTH3 gene in MDR development is through its proapoptotic potential that is regulated by multiple mechanisms at the transcription level, and one of these mechanisms is linked to the p53 gene.

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The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis

Cited by 335 publications

References 48 publications

P-glycoprotein inhibits caspase-8 activation but not formation of the death inducing signal complex (disc) following Fas ligation

P-glycoprotein inhibits caspase-8 activation but not formation of the death inducing signal complex (disc) following Fas ligation

MYCN Enhances P-gp/MDR1 Gene Expression in the Human Metastatic Neuroblastoma IGR-N-91 Model

WTH3 is a direct target of the p53 protein

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