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

DOI Web Site 2 Citations
  • Chentao Ge
    Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018 Hangzhou, China;
  • Hemiao Huang
    Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018 Hangzhou, China;
  • Feiyan Huang
    Clinical Laboratory, Zhejiang Provincial Hospital of TCM, 310006 Hangzhou, China;
  • Tianxin Yang
    Department of Hematology, Zhejiang Province People’s Hospital, 310014 Hangzhou, China;
  • Tengfei Zhang
    Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018 Hangzhou, China;
  • Hongzhang Wu
    Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018 Hangzhou, China;
  • Hanwei Zhou
    Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018 Hangzhou, China;
  • Qi Chen
    Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018 Hangzhou, China;
  • Yue Shi
    Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018 Hangzhou, China;
  • Yanfang Sun
    Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018 Hangzhou, China;
  • Liangjue Liu
    Clinical Laboratory, Zhejiang Provincial Hospital of TCM, 310006 Hangzhou, China;
  • Xi Wang
    Department of Oncology, The People’s Liberation Army No. 903rd Hospital, 310013 Hangzhou, China;
  • Richard B. Pearson
    Oncogenic Signalling and Growth Control Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia;
  • Yihai Cao
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden
  • Jian Kang
    Oncogenic Signalling and Growth Control Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia;
  • Caiyun Fu
    Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018 Hangzhou, China;

Abstract

<jats:p>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.</jats:p>

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