Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis

Wei Ching Huang, Cheng Chieh Tsai, Chia Ling Chen, Tsai Yun Chen, Ya Ping Chen, Yee Shin Lin, Pei Jung Lu, Chun Mao Lin, Shwu Huey Wang, Chiung Wen Tsao, Chi Yun Wang, Yi Lin Cheng, Chia Yuan Hsieh, Po Chun Tseng, Chiou Feng Lin

Research output: Contribution to journalArticle

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Abstract

Inactivation of glycogen synthase kinase (GSK)-3 has been implicated in cancer progression. Previously, we showed an abundance of inactive GSK-3 in the human chronic myeloid leukemia (CML) cell line. CML is a hematopoietic malignancy caused by an oncogenic Bcr-Abl tyrosine kinase. In Bcr-Abl signaling, the role of GSK-3 is not well defined. Here, we report that enforced expression of constitutively active GSK-3 reduced proliferation and increased Bcr-Abl inhibitioninduced apoptosis by nearly 1-fold. Bcr-Abl inhibition activated GSK-3 and GSK-3-dependent apoptosis. Inactivation of GSK-3 by Bcr-Abl activity is, therefore, confirmed. To reactivate GSK-3, we used glucosylceramide synthase (GCS) inhibitor PDMP to accumulate endogenous ceramide, a tumor-suppressor sphingolipid and a potent GSK-3 activator. We found that either PDMP or silence of GCS increased Bcr-Abl inhibitioninduced GSK-3 activation and apoptosis. Furthermore, PDMP sensitized the most clinical problematic drugresistant CML T315I mutant to Bcr-Abl inhibitor GNF- 2-, imatinib-, or nilotinib-induced apoptosis by >5-fold. Combining PDMP and GNF-2 eliminated transplanted- CML-T315I-mutants in vivo and dose dependently sensitized primary cells from CML T315I patients to GNF-2-induced proliferation inhibition and apoptosis. The synergistic efficacy was Bcr-Abl restricted and correlated to increased intracellular ceramide levels and acted through GSK-3-mediated apoptosis. This study suggests a feasible novel anti-CML strategy by accumulating endogenous ceramide to reactivate GSK-3 and abrogate drug resistance.

Original languageEnglish
Pages (from-to)3661-3673
Number of pages13
JournalFASEB Journal
Volume25
Issue number10
DOIs
Publication statusPublished - 2011 Oct 1

Fingerprint

ceramide glucosyltransferase
Glycogen Synthase Kinase 3
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Apoptosis
Ceramides
RV 538
bcr-abl Fusion Proteins

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Huang, Wei Ching ; Tsai, Cheng Chieh ; Chen, Chia Ling ; Chen, Tsai Yun ; Chen, Ya Ping ; Lin, Yee Shin ; Lu, Pei Jung ; Lin, Chun Mao ; Wang, Shwu Huey ; Tsao, Chiung Wen ; Wang, Chi Yun ; Cheng, Yi Lin ; Hsieh, Chia Yuan ; Tseng, Po Chun ; Lin, Chiou Feng. / Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis. In: FASEB Journal. 2011 ; Vol. 25, No. 10. pp. 3661-3673.
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abstract = "Inactivation of glycogen synthase kinase (GSK)-3 has been implicated in cancer progression. Previously, we showed an abundance of inactive GSK-3 in the human chronic myeloid leukemia (CML) cell line. CML is a hematopoietic malignancy caused by an oncogenic Bcr-Abl tyrosine kinase. In Bcr-Abl signaling, the role of GSK-3 is not well defined. Here, we report that enforced expression of constitutively active GSK-3 reduced proliferation and increased Bcr-Abl inhibitioninduced apoptosis by nearly 1-fold. Bcr-Abl inhibition activated GSK-3 and GSK-3-dependent apoptosis. Inactivation of GSK-3 by Bcr-Abl activity is, therefore, confirmed. To reactivate GSK-3, we used glucosylceramide synthase (GCS) inhibitor PDMP to accumulate endogenous ceramide, a tumor-suppressor sphingolipid and a potent GSK-3 activator. We found that either PDMP or silence of GCS increased Bcr-Abl inhibitioninduced GSK-3 activation and apoptosis. Furthermore, PDMP sensitized the most clinical problematic drugresistant CML T315I mutant to Bcr-Abl inhibitor GNF- 2-, imatinib-, or nilotinib-induced apoptosis by >5-fold. Combining PDMP and GNF-2 eliminated transplanted- CML-T315I-mutants in vivo and dose dependently sensitized primary cells from CML T315I patients to GNF-2-induced proliferation inhibition and apoptosis. The synergistic efficacy was Bcr-Abl restricted and correlated to increased intracellular ceramide levels and acted through GSK-3-mediated apoptosis. This study suggests a feasible novel anti-CML strategy by accumulating endogenous ceramide to reactivate GSK-3 and abrogate drug resistance.",
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Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis. / Huang, Wei Ching; Tsai, Cheng Chieh; Chen, Chia Ling; Chen, Tsai Yun; Chen, Ya Ping; Lin, Yee Shin; Lu, Pei Jung; Lin, Chun Mao; Wang, Shwu Huey; Tsao, Chiung Wen; Wang, Chi Yun; Cheng, Yi Lin; Hsieh, Chia Yuan; Tseng, Po Chun; Lin, Chiou Feng.

In: FASEB Journal, Vol. 25, No. 10, 01.10.2011, p. 3661-3673.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis

AU - Huang, Wei Ching

AU - Tsai, Cheng Chieh

AU - Chen, Chia Ling

AU - Chen, Tsai Yun

AU - Chen, Ya Ping

AU - Lin, Yee Shin

AU - Lu, Pei Jung

AU - Lin, Chun Mao

AU - Wang, Shwu Huey

AU - Tsao, Chiung Wen

AU - Wang, Chi Yun

AU - Cheng, Yi Lin

AU - Hsieh, Chia Yuan

AU - Tseng, Po Chun

AU - Lin, Chiou Feng

PY - 2011/10/1

Y1 - 2011/10/1

N2 - Inactivation of glycogen synthase kinase (GSK)-3 has been implicated in cancer progression. Previously, we showed an abundance of inactive GSK-3 in the human chronic myeloid leukemia (CML) cell line. CML is a hematopoietic malignancy caused by an oncogenic Bcr-Abl tyrosine kinase. In Bcr-Abl signaling, the role of GSK-3 is not well defined. Here, we report that enforced expression of constitutively active GSK-3 reduced proliferation and increased Bcr-Abl inhibitioninduced apoptosis by nearly 1-fold. Bcr-Abl inhibition activated GSK-3 and GSK-3-dependent apoptosis. Inactivation of GSK-3 by Bcr-Abl activity is, therefore, confirmed. To reactivate GSK-3, we used glucosylceramide synthase (GCS) inhibitor PDMP to accumulate endogenous ceramide, a tumor-suppressor sphingolipid and a potent GSK-3 activator. We found that either PDMP or silence of GCS increased Bcr-Abl inhibitioninduced GSK-3 activation and apoptosis. Furthermore, PDMP sensitized the most clinical problematic drugresistant CML T315I mutant to Bcr-Abl inhibitor GNF- 2-, imatinib-, or nilotinib-induced apoptosis by >5-fold. Combining PDMP and GNF-2 eliminated transplanted- CML-T315I-mutants in vivo and dose dependently sensitized primary cells from CML T315I patients to GNF-2-induced proliferation inhibition and apoptosis. The synergistic efficacy was Bcr-Abl restricted and correlated to increased intracellular ceramide levels and acted through GSK-3-mediated apoptosis. This study suggests a feasible novel anti-CML strategy by accumulating endogenous ceramide to reactivate GSK-3 and abrogate drug resistance.

AB - Inactivation of glycogen synthase kinase (GSK)-3 has been implicated in cancer progression. Previously, we showed an abundance of inactive GSK-3 in the human chronic myeloid leukemia (CML) cell line. CML is a hematopoietic malignancy caused by an oncogenic Bcr-Abl tyrosine kinase. In Bcr-Abl signaling, the role of GSK-3 is not well defined. Here, we report that enforced expression of constitutively active GSK-3 reduced proliferation and increased Bcr-Abl inhibitioninduced apoptosis by nearly 1-fold. Bcr-Abl inhibition activated GSK-3 and GSK-3-dependent apoptosis. Inactivation of GSK-3 by Bcr-Abl activity is, therefore, confirmed. To reactivate GSK-3, we used glucosylceramide synthase (GCS) inhibitor PDMP to accumulate endogenous ceramide, a tumor-suppressor sphingolipid and a potent GSK-3 activator. We found that either PDMP or silence of GCS increased Bcr-Abl inhibitioninduced GSK-3 activation and apoptosis. Furthermore, PDMP sensitized the most clinical problematic drugresistant CML T315I mutant to Bcr-Abl inhibitor GNF- 2-, imatinib-, or nilotinib-induced apoptosis by >5-fold. Combining PDMP and GNF-2 eliminated transplanted- CML-T315I-mutants in vivo and dose dependently sensitized primary cells from CML T315I patients to GNF-2-induced proliferation inhibition and apoptosis. The synergistic efficacy was Bcr-Abl restricted and correlated to increased intracellular ceramide levels and acted through GSK-3-mediated apoptosis. This study suggests a feasible novel anti-CML strategy by accumulating endogenous ceramide to reactivate GSK-3 and abrogate drug resistance.

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