Hexamethylene amiloride induces lysosome-mediated cell death in multiple myeloma through transcription factor E3.

IF 6.1 2区 生物学 Q1 CELL BIOLOGY
Nianhui Yang, Zexuan Dong, Weihao Xiao, Suqi Deng, Yizhen Li, Lei Hua, Yue Li, Yingying Wu, Kexiu Huang, Wei Zhou, Hua Wang, Yonghua Li, Juan Du, Hui Zeng
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引用次数: 0

Abstract

Multiple myeloma (MM) is the second common hematological malignancy characterized by the abnormal proliferation of plasma cells. Although advances in the past decades have led to improved outcomes and longer survival, MM remains largely incurable. New targets and targeted therapy may help to achieve better outcomes. Proton exporter NHE1 is highly expressed by tumor cells to maintain pH gradient for their survival and its inhibitor Hexamethylene amiloride (HA) has been demonstrated anti-tumor effect. However, whether HA could inhibit MM remains unknown. In this study, we firstly demonstrated that elevated expression level of NHE1 is associated with poor prognosis of MM. Moreover, the NHE1 inhibitor HA inhibited growth and induced apoptosis effectively in both MM cell lines and primary bone marrow cells from MM patients. Mechanistically, inhibitory effect was achieved partially through TFE3-mediated lysosomal production. With a MM xenograft mouse model, we verified that HA has a significant anti MM effect in vivo. Importantly, HA induced apoptosis of the carfilzomib-resistant MM cells and enhanced the effect of carfilzomib in MM. In summary, we demonstrated that NHE1 inhibitor HA can effectively inhibit MM growth both in vitro and in vivo, providing a new therapeutic strategy for improved outcome of de novo and resistant MM.

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来源期刊
Cell Death Discovery
Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
8.30
自引率
1.40%
发文量
468
审稿时长
9 weeks
期刊介绍: Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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