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

研究成果: 雜誌貢獻文章同行評審

36 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)3661-3673
頁數13
期刊FASEB Journal
25
發行號10
DOIs
出版狀態已發佈 - 十月 2011

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

指紋 深入研究「Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis」主題。共同形成了獨特的指紋。

引用此