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

Ching Huang Wu, Mojgan Rastegar, John Gordon, Ahmad R. Safa

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Abstract

In this study, we examined whether exogenous β2-microglobulin (β2m) can induce apoptosis in the drug sensitive HL-60 leukemia cell line and its drug resistant variants and investigated the molecular mechanism of β2m-induced apoptosis. Our data revealed that β2m is very significantly down-regulated in two multidrug resistant variants of the HL-60 cells: (a) the MRP1-bearing, Bax-deficient HL-60/ADR cell line, and (b) the P-glycoprotein (P-gp) overexpressing HL-60/VCR cell line. However, exogenous β2m induced similar levels of apoptosis in HL-60 cells and these drug resistant variants. β2m-induced apoptosis in HL-60 and HL-60/VCR cells was associated with decreased mitochondrial membrane potential (Δψm) but did not affect Δψm in HL-60/ADR cells. Surprisingly, cyclosporin A (CsA), a known inhibitor of the mitochondrial permeability transition (MPT) pore, inhibited β2m-induced apoptosis in HL-60/ADR cells but not in HL-60 and HL-60/VCR cells, suggesting that the pro-apoptotic effect of β2m in these cells is not through MPT pore formation. Furthermore, β2m induced the release of cytochrome c and the apoptosis-inducing factor (AIF) from mitochondria in HL-60 and HL-60/VCR cells, but not in HL-60/ADR cells. Additionally, z-VAD-fmk, a general inhibitor of caspases which inhibited cytochrome c release in HL-60 and HL-60/VCR cells, had no effect on AIF release in any of these cell lines, but inhibited β2m-induced apoptosis in all three cell lines. However, Western blot analysis revealed that caspases-1, -3, -6, -8, and -9 are not activated during β2m-induced apoptosis in these cells. Therefore, β2m-induces apoptosis through an unknown caspase-dependent mitochondrial pathway in HL-60 and HL-60/VCR cells and by a Bax-independent, nonmitochodrial, caspase-dependent pathway in HL-60/ADR cells.

Original languageEnglish (US)
Pages (from-to)7006-7020
Number of pages15
JournalOncogene
Volume20
Issue number48
DOIs
StatePublished - Oct 25 2001

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Keywords

  • β-microglobulin
  • Apoptosis
  • Caspases
  • Leukemia
  • Multidrug resistance

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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