Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells

Li Pin Kao, Samy A.F. Morad, Traci S. Davis, Matthew R. MacDougall, Miki Kassai, Noha Abdelmageed, Todd E. Fox, Mark Kester, Thomas P. Loughran, Jose L. Abad, Gemma Fabrias, Su Fern Tan, David J. Feith, David Claxton, Sarah Spiegel, Kelsey H. Fisher-Wellman, Myles C. Cabot

Research output: Contribution to journalArticle

Abstract

The combination of daunorubicin (dnr) and cytarabine (Ara-C) is a cornerstone of treatment for acute myelogenous leukemia (AML); resistance to these drugs is a major cause of treatment failure. Ceramide, a sphingolipid (SL), plays a critical role in cancer cell apoptosis in response to chemotherapy. Here, we investigated the effects of chemotherapy selection pressure with Ara-C and dnr on SL composition and enzyme activity in the AML cell line HL-60. Resistant cells, those selected for growth in Ara-C- and dnr-containing medium (HL-60/Ara-C and HL-60/dnr, respectively), demonstrated upregulated expression and activity of glucosylceramide synthase, acid ceramidase (AC), and sphingosine kinase 1 (SPHK1); were more resistant to ceramide than parental cells; and displayed sensitivity to inhibitors of SL metabolism. Lipidomic analysis revealed a general ceramide deficit and a profound upswing in levels of sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) in HL-60/dnr cells versus parental and HL-60/Ara-C cells. Both chemotherapyselected cells also exhibited comprehensive upregulations in mitochondrial biogenesis consistent with heightened reliance on oxidative phosphorylation, a property that was partially reversed by exposure to AC and SPHK1 inhibitors and that supports a role for the phosphorylation system in resistance. In summary, dnr and Ara-C selection pressure induces acute reductions in ceramide levels and large increases in S1P and C1P, concomitant with cell resilience bolstered by enhanced mitochondrial remodeling. Thus, strategic control of ceramide metabolism and further research to define mitochondrial perturbations that accompany the drug-resistant phenotype offer new opportunities for developing therapies that regulate cancer growth.

Original languageEnglish (US)
Pages (from-to)1590-1602
Number of pages13
JournalJournal of Lipid Research
Volume60
Issue number9
DOIs
StatePublished - Jan 1 2019

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Sphingolipids
Chemotherapy
HL-60 Cells
Cytarabine
Daunorubicin
Energy Metabolism
Ceramides
Pressure
Drug Therapy
Chemical analysis
Acid Ceramidase
ceramide glucosyltransferase
Metabolism
Acute Myeloid Leukemia
Cells
Phosphorylation
Oxidative Phosphorylation
Enzyme activity
Organelle Biogenesis
Growth

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Kao, L. P., Morad, S. A. F., Davis, T. S., MacDougall, M. R., Kassai, M., Abdelmageed, N., ... Cabot, M. C. (2019). Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells. Journal of Lipid Research, 60(9), 1590-1602. https://doi.org/10.1194/jlr.RA119000251
Kao, Li Pin ; Morad, Samy A.F. ; Davis, Traci S. ; MacDougall, Matthew R. ; Kassai, Miki ; Abdelmageed, Noha ; Fox, Todd E. ; Kester, Mark ; Loughran, Thomas P. ; Abad, Jose L. ; Fabrias, Gemma ; Tan, Su Fern ; Feith, David J. ; Claxton, David ; Spiegel, Sarah ; Fisher-Wellman, Kelsey H. ; Cabot, Myles C. / Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells. In: Journal of Lipid Research. 2019 ; Vol. 60, No. 9. pp. 1590-1602.
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abstract = "The combination of daunorubicin (dnr) and cytarabine (Ara-C) is a cornerstone of treatment for acute myelogenous leukemia (AML); resistance to these drugs is a major cause of treatment failure. Ceramide, a sphingolipid (SL), plays a critical role in cancer cell apoptosis in response to chemotherapy. Here, we investigated the effects of chemotherapy selection pressure with Ara-C and dnr on SL composition and enzyme activity in the AML cell line HL-60. Resistant cells, those selected for growth in Ara-C- and dnr-containing medium (HL-60/Ara-C and HL-60/dnr, respectively), demonstrated upregulated expression and activity of glucosylceramide synthase, acid ceramidase (AC), and sphingosine kinase 1 (SPHK1); were more resistant to ceramide than parental cells; and displayed sensitivity to inhibitors of SL metabolism. Lipidomic analysis revealed a general ceramide deficit and a profound upswing in levels of sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) in HL-60/dnr cells versus parental and HL-60/Ara-C cells. Both chemotherapyselected cells also exhibited comprehensive upregulations in mitochondrial biogenesis consistent with heightened reliance on oxidative phosphorylation, a property that was partially reversed by exposure to AC and SPHK1 inhibitors and that supports a role for the phosphorylation system in resistance. In summary, dnr and Ara-C selection pressure induces acute reductions in ceramide levels and large increases in S1P and C1P, concomitant with cell resilience bolstered by enhanced mitochondrial remodeling. Thus, strategic control of ceramide metabolism and further research to define mitochondrial perturbations that accompany the drug-resistant phenotype offer new opportunities for developing therapies that regulate cancer growth.",
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Kao, LP, Morad, SAF, Davis, TS, MacDougall, MR, Kassai, M, Abdelmageed, N, Fox, TE, Kester, M, Loughran, TP, Abad, JL, Fabrias, G, Tan, SF, Feith, DJ, Claxton, D, Spiegel, S, Fisher-Wellman, KH & Cabot, MC 2019, 'Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells', Journal of Lipid Research, vol. 60, no. 9, pp. 1590-1602. https://doi.org/10.1194/jlr.RA119000251

Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells. / Kao, Li Pin; Morad, Samy A.F.; Davis, Traci S.; MacDougall, Matthew R.; Kassai, Miki; Abdelmageed, Noha; Fox, Todd E.; Kester, Mark; Loughran, Thomas P.; Abad, Jose L.; Fabrias, Gemma; Tan, Su Fern; Feith, David J.; Claxton, David; Spiegel, Sarah; Fisher-Wellman, Kelsey H.; Cabot, Myles C.

In: Journal of Lipid Research, Vol. 60, No. 9, 01.01.2019, p. 1590-1602.

Research output: Contribution to journalArticle

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T1 - Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells

AU - Kao, Li Pin

AU - Morad, Samy A.F.

AU - Davis, Traci S.

AU - MacDougall, Matthew R.

AU - Kassai, Miki

AU - Abdelmageed, Noha

AU - Fox, Todd E.

AU - Kester, Mark

AU - Loughran, Thomas P.

AU - Abad, Jose L.

AU - Fabrias, Gemma

AU - Tan, Su Fern

AU - Feith, David J.

AU - Claxton, David

AU - Spiegel, Sarah

AU - Fisher-Wellman, Kelsey H.

AU - Cabot, Myles C.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The combination of daunorubicin (dnr) and cytarabine (Ara-C) is a cornerstone of treatment for acute myelogenous leukemia (AML); resistance to these drugs is a major cause of treatment failure. Ceramide, a sphingolipid (SL), plays a critical role in cancer cell apoptosis in response to chemotherapy. Here, we investigated the effects of chemotherapy selection pressure with Ara-C and dnr on SL composition and enzyme activity in the AML cell line HL-60. Resistant cells, those selected for growth in Ara-C- and dnr-containing medium (HL-60/Ara-C and HL-60/dnr, respectively), demonstrated upregulated expression and activity of glucosylceramide synthase, acid ceramidase (AC), and sphingosine kinase 1 (SPHK1); were more resistant to ceramide than parental cells; and displayed sensitivity to inhibitors of SL metabolism. Lipidomic analysis revealed a general ceramide deficit and a profound upswing in levels of sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) in HL-60/dnr cells versus parental and HL-60/Ara-C cells. Both chemotherapyselected cells also exhibited comprehensive upregulations in mitochondrial biogenesis consistent with heightened reliance on oxidative phosphorylation, a property that was partially reversed by exposure to AC and SPHK1 inhibitors and that supports a role for the phosphorylation system in resistance. In summary, dnr and Ara-C selection pressure induces acute reductions in ceramide levels and large increases in S1P and C1P, concomitant with cell resilience bolstered by enhanced mitochondrial remodeling. Thus, strategic control of ceramide metabolism and further research to define mitochondrial perturbations that accompany the drug-resistant phenotype offer new opportunities for developing therapies that regulate cancer growth.

AB - The combination of daunorubicin (dnr) and cytarabine (Ara-C) is a cornerstone of treatment for acute myelogenous leukemia (AML); resistance to these drugs is a major cause of treatment failure. Ceramide, a sphingolipid (SL), plays a critical role in cancer cell apoptosis in response to chemotherapy. Here, we investigated the effects of chemotherapy selection pressure with Ara-C and dnr on SL composition and enzyme activity in the AML cell line HL-60. Resistant cells, those selected for growth in Ara-C- and dnr-containing medium (HL-60/Ara-C and HL-60/dnr, respectively), demonstrated upregulated expression and activity of glucosylceramide synthase, acid ceramidase (AC), and sphingosine kinase 1 (SPHK1); were more resistant to ceramide than parental cells; and displayed sensitivity to inhibitors of SL metabolism. Lipidomic analysis revealed a general ceramide deficit and a profound upswing in levels of sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) in HL-60/dnr cells versus parental and HL-60/Ara-C cells. Both chemotherapyselected cells also exhibited comprehensive upregulations in mitochondrial biogenesis consistent with heightened reliance on oxidative phosphorylation, a property that was partially reversed by exposure to AC and SPHK1 inhibitors and that supports a role for the phosphorylation system in resistance. In summary, dnr and Ara-C selection pressure induces acute reductions in ceramide levels and large increases in S1P and C1P, concomitant with cell resilience bolstered by enhanced mitochondrial remodeling. Thus, strategic control of ceramide metabolism and further research to define mitochondrial perturbations that accompany the drug-resistant phenotype offer new opportunities for developing therapies that regulate cancer growth.

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