Induction of p53-mediated transcription and apoptosis by exportin-1 (XPO1) inhibition in mantle cell lymphoma

被引：78

作者：

Yoshimura, Mariko ^{[1
]}

Ishizawa, Jo ^{[2
]}

Ruvolo, Vivian ^{[2
]}

Dilip, Archana ^{[2
]}

Quintas-Cardama, Alfonso ^{[2
]}

McDonnell, Timothy J. ^{[3
]}

Neelapu, Sattva S. ^{[4
]}

Kwak, Larry W. ^{[4
]}

Shacham, Sharon ^{[5
]}

Kauffman, Michael ^{[5
]}

Tabe, Yoko ^{[6
]}

Yokoo, Masako ^{[1
]}

Kimura, Shinya ^{[1
]}

Andreeff, Michael ^{[2
]}

Kojima, Kensuke ^{[1
,2
]}

机构：

[1] Saga Univ, Dept Med, Saga 8498501, Japan

[2] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USA

[5] Karyopharm Therapeut, Boston, MA USA

[6] Juntendo Univ, Sch Med, Dept Clin Lab Med, Tokyo 113, Japan

来源：

CANCER SCIENCE | 2014年 / 105卷 / 07期

基金：

美国国家卫生研究院;

关键词：

Apoptosis; KPT-SINE; mantle cell lymphoma; p53; XPO1; CHRONIC LYMPHOCYTIC-LEUKEMIA; NUCLEAR EXPORT; SELECTIVE INHIBITORS; TP53; MUTATION; CANCER-CELLS; P53; CRM1; EXPRESSION; TUMOR; MDM2;

D O I：

10.1111/cas.12430

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The nuclear transporter exportin-1 (XPO1) is highly expressed in mantle cell lymphoma (MCL) cells, and is believed to be associated with the pathogenesis of this disease. XPO1-selective inhibitors of nuclear export (SINE) compounds have been shown to induce apoptosis in MCL cells. Given that p53 is a cargo protein of XPO1, we sought to determine the significance of p53 activation through XPO1 inhibition in SINE-induced apoptosis of MCL cells. We investigated the prognostic impact of XPO1 expression in MCL cells using Oncomine analysis. The significance of p53 mutational/functional status on sensitivity to XPO1 inhibition in cell models and primary MCL samples, and the functional role of p53-mediated apoptosis signaling, were also examined. Increased XPO1 expression was associated with poor prognosis in MCL patients. The XPO1 inhibitor KPT-185 induced apoptosis in MCL cells through p53-dependent and -independent mechanisms, and p53 status was a critical determinant of its apoptosis induction. The KPT-185-induced, p53-mediated apoptosis in the MCL cells occurred in a transcription-dependent manner. Exportin-1 appears to influence patient survival in MCL, and the SINE XPO1 antagonist KPT-185 effectively activates p53-mediated transcription and apoptosis, which would provide a novel strategy for the therapy of MCL.

引用

页码：795 / 801

页数：7

共 40 条

[31] EXPRESSION OF CRM1 IN HUMAN GLIOMAS AND ITS SIGNIFICANCE IN P27 EXPRESSION AND CLINICAL PROGNOSIS [J].