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

36 Citations (Scopus)

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 - Oct 2011

Keywords

  • Ceramide
  • Drug resistance
  • Gatekeeper mutation

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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