Inhibition of Aurora kinases induces apoptosis and autophagy via AURKB/p70S6K/RPL15 axis in human leukemia cells.
Leukemia is a common malignancy of blood cells with poor prognosis in many patients. Aurora kinases, a family of serine/threonine kinases, play a key role in regulating cell division and mitosis and are linked to tumorigenesis, metastasis, and poor prognosis in many human cancers including leukemia and lymphoma. Danusertib (Danu) is a pan-inhibitor of Aurora kinases with few data available in leukemia therapy. This study aimed to identify new molecular targets for Aurora kinase inhibition in human leukemia cells using quantitative proteomic analysis followed by verification experiments. There were at least 2932 proteins responding to Danu treatment, including AURKB, p70S6K, and RPL15, and 603 functional proteins and 245 canonical signaling pathways were involved in regulating cell proliferation, metabolism, apoptosis, and autophagy. The proteomic data suggested that Danu-regulated RPL15 signaling might contribute to the cancer cell killing effect. Our verification experiments confirmed that Danu negatively regulated AURKB/p70S6K/RPL15 axis with the involvement of PI3K/Akt/mTOR, AMPK, and p38 MAPK signaling pathways, leading to the induction of apoptosis and autophagy in human leukemia cells. Further studies are warranted to verify the feasibility via targeting AURKB/p70S6K/RPL15 axis for leukemia therapy.
Department of Pediatrics, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Laboratory Animal Center, Guiyang Medical University, Guiyang 550004, China; Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA.
Si-Jia
SJ
He
Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Laboratory Animal Center, Guiyang Medical University, Guiyang 550004, China.
Li-Ping
LP
Shu
Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA.
Zhi-Wei
ZW
Zhou
Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
Tianxin
T
Yang
School of Medicine, Deakin University, Waurn Ponds, Victoria 3217, Australia.
Wei
W
Duan
Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing 100083, China.
Xueji
X
Zhang
Department of Pediatrics, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center & Sino-US Joint Laboratory for Medical Sciences, Laboratory Animal Center, Guiyang Medical University, Guiyang 550004, China. Electronic address: hzx@gmc.edu.cn.
Zhi-Xu
ZX
He
Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA; Department of Bioengineering and Biotechnology, College of Chemical Engineering, Huaqiao University, Xiamen, Fujian 361021, China. Electronic address: shufengzhou2006@hotmail.com.
Shu-Feng
SF
Zhou
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040901:Proteomics / Q000379:methods; D011720:Pyrazoles / Q000494:pharmacology*; D034622:RNA Interference; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001549:Benzamides; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D012269:Ribosomal Proteins; C043649:ribosomal protein L15; C576921:AURKB protein, human; D064107:Aurora Kinase B; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C523797:danusertib
AURKB/RPL15/p70S6K axis; Apoptosis; Aurora kinase; Autophagy; Danusertib; Leukemia