Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-κB-dependent P-glycoprotein upregulation

Su Fern Tan, Wendy Dunton, Xin Liu, Todd E. Fox, Samy A.F. Morad, Dhimant Desai, Kenichiro Doi, Mark R. Conaway, Shantu Amin, David Claxton, Hong-Gang Wang, Mark Kester, Myles C. Cabot, David J. Feith, Thomas P. Loughran

Research output: Contribution to journalArticle

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Abstract

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. More than half of older AML patients fail to respond to cytotoxic chemotherapy, and most responders relapse with drug-resistant disease. Failure to achieve complete remission can be partly attributed to the drug resistance advantage of AML blasts that frequently express P-glycoprotein (P-gp), an ATP-binding cassette transporter. Our previous work showed that elevated acid ceramidase (AC) levels in AML contribute to blast survival. Here, we investigated P-gp expression levels in AML relative to AC. Using parental HL-60 cells and drug-resistant derivatives as our model, we found that P-gp expression and efflux activity were highly upregulated in resistant derivatives. AC overexpression in HL-60 conferred resistance to the AML chemotherapeutic drugs, cytarabine, mitoxantrone, and daunorubicin, and was linked to P-gp upregulation. Furthermore, targeting AC through pharmacologic or genetic approaches decreased P-gp levels and increased sensitivity to chemotherapeutic drugs. Mechanistically, AC overexpression increased NF-κB activation whereas NF-kB inhibitors reduced P-gp levels, indicating that the NF-kappaB pathway contributes to AC-mediated modulation of P-gp expression. Hence, our data support an important role for AC in drug resistance as well as survival and suggest that sphingolipid targeting approaches may also impact drug resistance in AML.

Original languageEnglish (US)
Pages (from-to)1078-1086
Number of pages9
JournalJournal of Lipid Research
Volume60
Issue number6
DOIs
StatePublished - Jan 1 2019

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Acid Ceramidase
P-Glycoprotein
Drug Resistance
Acute Myeloid Leukemia
Up-Regulation
Pharmaceutical Preparations
NF-kappa B
Derivatives
Mitoxantrone
Sphingolipids
Daunorubicin
ATP-Binding Cassette Transporters
Chemotherapy
Survival
HL-60 Cells
Cytarabine
Leukemia
Chemical activation
Modulation
Recurrence

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Tan, Su Fern ; Dunton, Wendy ; Liu, Xin ; Fox, Todd E. ; Morad, Samy A.F. ; Desai, Dhimant ; Doi, Kenichiro ; Conaway, Mark R. ; Amin, Shantu ; Claxton, David ; Wang, Hong-Gang ; Kester, Mark ; Cabot, Myles C. ; Feith, David J. ; Loughran, Thomas P. / Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-κB-dependent P-glycoprotein upregulation. In: Journal of Lipid Research. 2019 ; Vol. 60, No. 6. pp. 1078-1086.
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title = "Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-κB-dependent P-glycoprotein upregulation",
abstract = "Acute myeloid leukemia (AML) is the most common acute leukemia in adults. More than half of older AML patients fail to respond to cytotoxic chemotherapy, and most responders relapse with drug-resistant disease. Failure to achieve complete remission can be partly attributed to the drug resistance advantage of AML blasts that frequently express P-glycoprotein (P-gp), an ATP-binding cassette transporter. Our previous work showed that elevated acid ceramidase (AC) levels in AML contribute to blast survival. Here, we investigated P-gp expression levels in AML relative to AC. Using parental HL-60 cells and drug-resistant derivatives as our model, we found that P-gp expression and efflux activity were highly upregulated in resistant derivatives. AC overexpression in HL-60 conferred resistance to the AML chemotherapeutic drugs, cytarabine, mitoxantrone, and daunorubicin, and was linked to P-gp upregulation. Furthermore, targeting AC through pharmacologic or genetic approaches decreased P-gp levels and increased sensitivity to chemotherapeutic drugs. Mechanistically, AC overexpression increased NF-κB activation whereas NF-kB inhibitors reduced P-gp levels, indicating that the NF-kappaB pathway contributes to AC-mediated modulation of P-gp expression. Hence, our data support an important role for AC in drug resistance as well as survival and suggest that sphingolipid targeting approaches may also impact drug resistance in AML.",
author = "Tan, {Su Fern} and Wendy Dunton and Xin Liu and Fox, {Todd E.} and Morad, {Samy A.F.} and Dhimant Desai and Kenichiro Doi and Conaway, {Mark R.} and Shantu Amin and David Claxton and Hong-Gang Wang and Mark Kester and Cabot, {Myles C.} and Feith, {David J.} and Loughran, {Thomas P.}",
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language = "English (US)",
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Tan, SF, Dunton, W, Liu, X, Fox, TE, Morad, SAF, Desai, D, Doi, K, Conaway, MR, Amin, S, Claxton, D, Wang, H-G, Kester, M, Cabot, MC, Feith, DJ & Loughran, TP 2019, 'Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-κB-dependent P-glycoprotein upregulation', Journal of Lipid Research, vol. 60, no. 6, pp. 1078-1086. https://doi.org/10.1194/jlr.M091876

Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-κB-dependent P-glycoprotein upregulation. / Tan, Su Fern; Dunton, Wendy; Liu, Xin; Fox, Todd E.; Morad, Samy A.F.; Desai, Dhimant; Doi, Kenichiro; Conaway, Mark R.; Amin, Shantu; Claxton, David; Wang, Hong-Gang; Kester, Mark; Cabot, Myles C.; Feith, David J.; Loughran, Thomas P.

In: Journal of Lipid Research, Vol. 60, No. 6, 01.01.2019, p. 1078-1086.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-κB-dependent P-glycoprotein upregulation

AU - Tan, Su Fern

AU - Dunton, Wendy

AU - Liu, Xin

AU - Fox, Todd E.

AU - Morad, Samy A.F.

AU - Desai, Dhimant

AU - Doi, Kenichiro

AU - Conaway, Mark R.

AU - Amin, Shantu

AU - Claxton, David

AU - Wang, Hong-Gang

AU - Kester, Mark

AU - Cabot, Myles C.

AU - Feith, David J.

AU - Loughran, Thomas P.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Acute myeloid leukemia (AML) is the most common acute leukemia in adults. More than half of older AML patients fail to respond to cytotoxic chemotherapy, and most responders relapse with drug-resistant disease. Failure to achieve complete remission can be partly attributed to the drug resistance advantage of AML blasts that frequently express P-glycoprotein (P-gp), an ATP-binding cassette transporter. Our previous work showed that elevated acid ceramidase (AC) levels in AML contribute to blast survival. Here, we investigated P-gp expression levels in AML relative to AC. Using parental HL-60 cells and drug-resistant derivatives as our model, we found that P-gp expression and efflux activity were highly upregulated in resistant derivatives. AC overexpression in HL-60 conferred resistance to the AML chemotherapeutic drugs, cytarabine, mitoxantrone, and daunorubicin, and was linked to P-gp upregulation. Furthermore, targeting AC through pharmacologic or genetic approaches decreased P-gp levels and increased sensitivity to chemotherapeutic drugs. Mechanistically, AC overexpression increased NF-κB activation whereas NF-kB inhibitors reduced P-gp levels, indicating that the NF-kappaB pathway contributes to AC-mediated modulation of P-gp expression. Hence, our data support an important role for AC in drug resistance as well as survival and suggest that sphingolipid targeting approaches may also impact drug resistance in AML.

AB - Acute myeloid leukemia (AML) is the most common acute leukemia in adults. More than half of older AML patients fail to respond to cytotoxic chemotherapy, and most responders relapse with drug-resistant disease. Failure to achieve complete remission can be partly attributed to the drug resistance advantage of AML blasts that frequently express P-glycoprotein (P-gp), an ATP-binding cassette transporter. Our previous work showed that elevated acid ceramidase (AC) levels in AML contribute to blast survival. Here, we investigated P-gp expression levels in AML relative to AC. Using parental HL-60 cells and drug-resistant derivatives as our model, we found that P-gp expression and efflux activity were highly upregulated in resistant derivatives. AC overexpression in HL-60 conferred resistance to the AML chemotherapeutic drugs, cytarabine, mitoxantrone, and daunorubicin, and was linked to P-gp upregulation. Furthermore, targeting AC through pharmacologic or genetic approaches decreased P-gp levels and increased sensitivity to chemotherapeutic drugs. Mechanistically, AC overexpression increased NF-κB activation whereas NF-kB inhibitors reduced P-gp levels, indicating that the NF-kappaB pathway contributes to AC-mediated modulation of P-gp expression. Hence, our data support an important role for AC in drug resistance as well as survival and suggest that sphingolipid targeting approaches may also impact drug resistance in AML.

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