Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 39, Pages 19635-19645Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1908998116
Keywords
neurokinin-1 receptor; oxidative stress; mitochondrial calcium fluxes; leukemia
Categories
Funding
- National Natural Science Foundation of China [81770176, 31470071]
- Zhejiang Provincial Nature Science Foundation of China [LY14C050003]
- New Century 151 Talent Project of Zhejiang Province
- 521 Talent Foundation
- Fundamental Research Funds of Zhejiang Sci-Tech University [2019Y001]
- Open Foundation from the Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province [ZJZLSYS004]
- National Health and Medical Research Council (NHMRC) of Australia [1058586, 1053792]
- National Health and Medical Research Council of Australia [1058586] Funding Source: NHMRC
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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 mitochondria! 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.
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