β2-microglobulin induces apoptosis in HL-60 human leukemia cell line and its multidrug resistant variants overexpressing MRP1 but lacking Bax or overexpressing P-glycoprotein

Wu, Ching Huang; Rastegar, Mojgan; Gordon, J. D. M.; Safa, Ahmad R.

doi:10.1038/sj.onc.1204893

Cited by 30 publications

(26 citation statements)

References 83 publications

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“…Our results show that the HL-60/ADR cells are about 122.5-14-and 8.5-fold more resistant to DOX, VCR and VBL, respectively, compared to their parental HL-60 cells (Table 1). Consistent with these data, we have previously reported that HL-60/ADR cells overexpress MRP1, but not P-gp (Wu et al, 2001).…”

Section: Drug Resistance Characteristics and Analysis Of Pr3 And Mrp1supporting

confidence: 90%

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

Gordon

Rastegar

et al. 2002

Oncogene

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We report here that expression of proteinase 3 (PR3), a serine protease, is down-regulated in the HL60/ADR multidrug resistant variant of the human myelogenous leukemia cell line HL-60, and that down-regulation of PR3 is associated with doxorubicin (DOX) resistance in these cells. To determine whether PR3 is involved in DOX-induced apoptosis in HL-60 cells, and whether its loss causes resistance to DOX, we inhibited PR3 expression by an anti-sense PR3 oligodeoxynucleotide and showed that inhibition of PR3 expression results in a significant reduction in DOX-induced DNA fragmentation and increased resistance to DOX-induced apoptosis. Our results revealed that PR3-mediated DOX-induced apoptosis in HL-60 cells is independent of the loss of mitochondrial membrane potential (DC m ) and activation of the caspase-8 and -9 pathways. Moreover, while PR3 is involved in the cleavage of caspase-3, PR3-mediated DOX-induced DNA fragmentation and apoptosis were not prevented by a specific inhibitor of caspase-3. These data suggest that activation of caspase-3 alone is not sufficient to trigger PR3-mediated DOX-induced apoptosis. Treatment with an anti-PR3 oligomer significantly decreased reactive oxygen species (ROS) generation in cells treated with low concentrations of DOX, revealing a role for PR3 in enhancing production of DOX-induced ROS. Moreover, DOX-induced apoptosis at 0.001 -0.01 mM was only inhibited in HL-60 cells pre-treated with the antioxidant N-acetyl-cysteine in the absence of anti-PR3, revealing that DOX-induced apoptosis in these cells is PR3-and ROS-dependent. Our results show that PR3 is involved in DOX-induced ROS-dependent apoptosis and that its loss is associated with resistance to DOX in HL-60 cells.

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Section: Drug Resistance Characteristics and Analysis Of Pr3 And Mrp1supporting

confidence: 90%

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

Gordon

Rastegar

et al. 2002

Oncogene

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“…HL-60/VCR cells in contrast were established as vincristineresistant cells and overexpress P-glycoprotein. Both multidrug resistant cell lines show enhanced efflux rates of various agents and hence display resistance to multiple anticancer drugs [46]. Both multidrug-resistant cell lines showed 35% apoptosis after 15 hrs in the presence of 50 µM PSI whereas HL-60 cells revealed an increase to 83% (Fig.…”

Section: Analysis Of Selected Proteins In Multidrug-resistant Hl-60 Cmentioning

confidence: 96%

Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI

Choi

Najafi

Safa

et al. 2008

Biochemical Pharmacology

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Proteasome inhibitors display potent anti-neoplastic and anti-angiogenic properties both in vitro and in vivo. The mechanisms, however, by which proteasome inhibitors kill tumor cells are still fairly elusive as is the molecular basis of resistance to treatment. To address these questions, we employed a high-throughput Western blotting procedure to analyze changes in a subproteome of ~800 proteins in the promyelocytic leukemia cell line HL-60 upon treatment with the proteasome inhibitor PSI (ZIle-Glu(OtBu)-Ala-Leu-aldehyde) and correlated the changes of selected target proteins with the changes in two multidrug resistant HL-60 variants. In total, 105 proteins were upregulated more than 1.5-fold after PSI treatment, while 79 proteins were downregulated. Activation of caspases-3 and -8, modulation of members of the Bcl-2 family as well as stimulation of stress signaling pathways was prominent during HL-60 apoptosis. We also identified changes in the abundance of proteins previously not known to be affected by proteasome inhibitors. In contrast, two multidrug resistant HL-60 cell lines, overexpressing either MRP1 or P-glycoprotein were largely resistant to PSI-induced apoptosis and could not be resensitized by the pharmacological inhibitors of the drug efflux pumps MK571 or PSC833. Drug resistance was also independent from the upregulation of Bad. Overexpression of multidrug resistance proteins, P-glycoprotein and MRP-1 is thus not sufficient to explain resistance of HL-60 cells to treatment with proteasome inhibitor PSI, which remains more closely related to a low level of Bax expression and to the inability to activate JNK. Alternative routes to the acquisition of resistance to PSI have therefore to be considered. Classification(1) Antibiotics and Chemotherapeutics

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“…All antibodies used were previously assessed by immunohistochemistry [for Dr4 and Dr5 (18); for cleaved caspase-3 (19)] or by Western blot analysis [for AIF (20); for cleaved caspase-3 (21)]. the antibodies p53 and Ki-67 are routinely used by the pathology Department.…”

Section: Patientmentioning

confidence: 99%

Expression of p53 and DR5 in normal and malignant tissues of colorectal cancer: Correlation with advanced stages

Perraud

Akil²,

Nouaille³

et al. 2011

Oncol Rep

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Abstract. Apoptosis has to be drastically controlled in organs with important cell turnover such as the colon. Deregulation of this process is often present in tumor progression. tissues of 82 patients treated for colorectal cancer (CrC) were analyzed using antibodies against AIF, p53, Dr4, Dr5, cleaved caspase-3 and the tUNeL method to detect apoptosis; whereas staining of Ki-67 was used as a proliferation marker. In situ immunohistochemical analyses were compared in non-tumor (Nt) cells from normal adjacent mucous membranes with tumor (t) cells from patients with stage I (n=6), stage II (n=35), stage III (n=27) and stage IV (n=14) CrC. results were correlated with the tumor stages and the treatment response of patients to improve the understanding of CrC development. p53 and Dr5 expression decreased progressively with CrC stage, suggesting that these proteins are important markers of advanced tumor stages. Moreover, p53 appears as a prognostic factor to predict recurrence-free survival. Including the detection of p53 and Dr5 for establishing the diagnosis of CrC and adapting the treatment to each patient is strongly suggested by our work.

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β2-microglobulin induces apoptosis in HL-60 human leukemia cell line and its multidrug resistant variants overexpressing MRP1 but lacking Bax or overexpressing P-glycoprotein

Cited by 30 publications

References 83 publications

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI

Expression of p53 and DR5 in normal and malignant tissues of colorectal cancer: Correlation with advanced stages

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