2. Academic Validation
  3. Neurokinin-1 receptor is an effective target for treating leukemia by inducing oxidative stress through mitochondrial calcium overload

Neurokinin-1 receptor is an effective target for treating leukemia by inducing oxidative stress through mitochondrial calcium overload

  • Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19635-19645. doi: 10.1073/pnas.1908998116.
Chentao Ge 1,  Hemiao Huang 1,  Feiyan Huang 2,  Tianxin Yang 3,  Tengfei Zhang 1,  Hongzhang Wu 1,  Hanwei Zhou 1,  Qi Chen 1,  Yue Shi 1,  Yanfang Sun 1,  Liangjue Liu 2,  Xi Wang 4,  Richard B Pearson 5 6,  Yihai Cao 7,  Jian Kang 5 6,  Caiyun Fu 8
Affiliations

Affiliations

  • 1 Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018 Hangzhou, China.
  • 2 Clinical Laboratory, Zhejiang Provincial Hospital of TCM, 310006 Hangzhou, China.
  • 3 Department of Hematology, Zhejiang Province People's Hospital, 310014 Hangzhou, China.
  • 4 Department of Oncology, The People's Liberation Army No. 903rd Hospital, 310013 Hangzhou, China.
  • 5 Oncogenic Signalling and Growth Control Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; fucy03@zstu.edu.cn jian.kang@petermac.org yihai.cao@ki.se rick.pearson@petermac.org.
  • 6 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3000, Australia.
  • 7 Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden fucy03@zstu.edu.cn jian.kang@petermac.org yihai.cao@ki.se rick.pearson@petermac.org.
  • 8 Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018 Hangzhou, China; fucy03@zstu.edu.cn jian.kang@petermac.org yihai.cao@ki.se rick.pearson@petermac.org.
PMID: 31488714 DOI: 10.1073/pnas.1908998116
Abstract

Substance P (SP) regulates multiple biological processes through its high-affinity neurokinin-1 receptor (NK-1R). While the SP/NK-1R signaling axis is involved in the pathogenesis of solid Cancer, the role of this signaling pathway in hematological malignancy remains unknown. Here, we demonstrate that NK-1R expression is markedly elevated in the white blood cells from acute myeloid leukemia patients and a panel of human leukemia cell lines. Blocking NK-1R induces Apoptosis in vitro and in vivo via increase of mitochondrial Reactive Oxygen Species. This oxidative stress was triggered by rapid calcium flux from the endoplasmic reticulum into mitochondria and, consequently, impairment of mitochondrial function, a mechanism underlying the cytotoxicity of NK-1R antagonists. Besides Anticancer activity, blocking NK-1R produces a potent antinociceptive effect in myeloid leukemia-induced bone pain by alleviating inflammation and inducing Apoptosis. These findings thus raise the exciting possibility that the NK-1R antagonists, drugs currently used in the clinic for preventing chemotherapy-induced nausea and vomiting, may provide a therapeutic option for treating human myeloid leukemia.

Keywords

leukemia; mitochondrial calcium fluxes; neurokinin-1 receptor; oxidative stress.

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