演題詳細

一般口演 / Oral Session

【E】一般口演 19 (Oral Session 19) :AML:Mechanism of Therapeutic Agent

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日程
2013年10月11日(金)
時間
14:25 - 15:25
会場
第4会場 / Room No.4 (さっぽろ芸文館 3F 黎明)
座長・司会
小林 正夫 (Masao Kobayashi):1
1:Department of Pediatrics, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan
 
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A novel proteasome independent target of bortezomib in leukemia cells

演題番号 : OS-1-98

Chun-Yu Liu (劉 峻宇):1、Chung-Wai Shiau:2、Kuen-Feng Chen:3、Hsin-Yu Kuo:1、Hui-Chuan Yu:3、Hsiang-Po Huang:3、Cheng-Hwai Tzeng:1、Po-Min Chen:1

1:Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan、2:Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan、3:Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

 

Relapsed or refractory leukemia has poor outcome and novel therapy is the unmet need. Bortezomib, a proteasome inhibitor, has excellent clinical anti-cancer activity in multiple myeloma and mantle cell lymphoma. Many studies have shown bortezomib exerts different cytotoxic effect among various cancers (solid tumors and hematological malignancies), suggesting the drug mechanism of action may not necessary depends on bortezomib’s proteasome inhibitory effect. We recently discovered that a novel Cancerous Inhibitor of PP2A (CIP2A), may be an important molecular determinant of bortezomib-induced apoptosis (Oncogene 2010, Hematologica 2012, and Plos One 2012). CIP2A is overexpressed in several human malignancies including leukemia and is a newly discovered inhibitor of PP2A. PP2A is a protein phosphatase that regulates cell proliferation via dephosphorylation of oncogenic kinases such as Akt and is believed to function as a tumor suppressor. CIP2A has been shown to promote anchorage-independent cell growth and in vivo tumor formation by inhibiting PP2A activity toward c-Myc. Importantly, CIP2A has been found to be associated with clinical aggressiveness in leukemia cells. Our data showed bortezomib enhanced PP2A activity by down-regulating CIP2A expression and this further down-regulated p-Akt and induced apoptosis in cancer cells. Importantly, this CIP2A-PP2A-p-Akt mechanism by bortezomib is independent to its proteasome inhibition. We designated a bortezomib derivative (Δbortezomib), which shows less potent proteasome inhibition but also down-regulates CIP2A and has similar or even more potent anti-tumor activity than bortezomib. Collectively, our data suggest that CIP2A is a novel molecular target of bortezomib in leukemia cells and targeting CIP2A-PP2A-p-Akt signaling may be a potential therapeutic anti-leukemia strategy.

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