Journal
CANCER SCIENCE
Volume 105, Issue 7, Pages 795-801Publisher
WILEY-BLACKWELL
DOI: 10.1111/cas.12430
Keywords
Apoptosis; KPT-SINE; mantle cell lymphoma; p53; XPO1
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Funding
- National Institutes of Health Lymphoma SPORE [CA136411, P50CA136411]
- Leukemia SPORE [CA100632]
- P01 The Therapy of AML [CA55164]
- Cancer Center Support Grant [CA16672]
- Paul and Mary Haas Chair in Genetics
- Osaka Cancer Research Foundation
- Japan Leukemia Research Fund
- Ministry of Education, Culture, Sports, Science and Technology in Japan
- Fredrick B. Hagemeister Research Fund
- Grants-in-Aid for Scientific Research [24501306] Funding Source: KAKEN
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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.
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