TY - JOUR
T1 - Lymphocyte antigen 6K signaling to aurora kinase promotes advancement of the cell cycle and the growth of cancer cells, which is inhibited by LY6K-NSC243928 interaction
AU - Selvanesan, Benson Chellakkan
AU - Varghese, Sheelu
AU - Andrys-Olek, Justyna
AU - Arriaza, Ricardo Hernandez
AU - Prakash, Rahul
AU - Tiwari, Purushottam Babu
AU - Hupalo, Daniel
AU - Gusev, Yuriy
AU - Patel, Megha Nitin
AU - Contente, Sara
AU - Sanda, Miloslav
AU - Uren, Aykut
AU - Wilkerson, Matthew D.
AU - Dalgard, Clifton Lee
AU - Shimizu, Linda S.
AU - Chruszcz, Maksymilian
AU - Borowski, Tomasz
AU - Upadhyay, Geeta
N1 - Funding Information:
R01CA227694 and R21CA256424, National Institutes of Health (NIH), National Cancer Institute (NCI), USA.Antibody Characterization Program, Clinical Proteomics Tumor Analysis Consortium (CPTAC), NIH, NCI, USA.VPR-NFP-74-9824, Uniformed Services University of the Health Sciences (USUHS), USA.The Polish Grid Infrastructure, Cracow, Poland.P30CA51008, NIH, NCI and 1S10OD019982-01, OD, NIH, USA.
Publisher Copyright:
© 2023
PY - 2023/4/1
Y1 - 2023/4/1
N2 - Lymphocyte antigen 6K (LY6K) is a small GPI-linked protein that is normally expressed in testes. Increased expression of LY6K is significantly associated with poor survival outcomes in many solid cancers, including cancers of the breast, ovary, gastrointestinal tract, head and neck, brain, bladder, and lung. LY6K is required for ERK-AKT and TGF-β pathways in cancer cells and is required for in vivo tumor growth. In this report, we describe a novel role for LY6K in mitosis and cytokinesis through aurora B kinase and its substrate histone H3 signaling axis. Further, we describe the structural basis of the molecular interaction of small molecule NSC243928 with LY6K protein and the disruption of LY6K-aurora B signaling in cell cycle progression due to LY6K-NSC243928 interaction. Overall, disruption of LY6K function via NSC243928 led to failed cytokinesis, multinucleated cells, DNA damage, senescence, and apoptosis of cancer cells. LY6K is not required for vital organ function, thus inhibition of LY6K signaling is an ideal therapeutic approach for hard-to-treat cancers that lack targeted therapy such as triple-negative breast cancer.
AB - Lymphocyte antigen 6K (LY6K) is a small GPI-linked protein that is normally expressed in testes. Increased expression of LY6K is significantly associated with poor survival outcomes in many solid cancers, including cancers of the breast, ovary, gastrointestinal tract, head and neck, brain, bladder, and lung. LY6K is required for ERK-AKT and TGF-β pathways in cancer cells and is required for in vivo tumor growth. In this report, we describe a novel role for LY6K in mitosis and cytokinesis through aurora B kinase and its substrate histone H3 signaling axis. Further, we describe the structural basis of the molecular interaction of small molecule NSC243928 with LY6K protein and the disruption of LY6K-aurora B signaling in cell cycle progression due to LY6K-NSC243928 interaction. Overall, disruption of LY6K function via NSC243928 led to failed cytokinesis, multinucleated cells, DNA damage, senescence, and apoptosis of cancer cells. LY6K is not required for vital organ function, thus inhibition of LY6K signaling is an ideal therapeutic approach for hard-to-treat cancers that lack targeted therapy such as triple-negative breast cancer.
KW - Aurora B
KW - LY6K
KW - NSC243928
KW - Triple negative breast cancer
UR - http://www.scopus.com/inward/record.url?scp=85149002814&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85149002814&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2023.216094
DO - 10.1016/j.canlet.2023.216094
M3 - Article
C2 - 36805500
AN - SCOPUS:85149002814
SN - 0304-3835
VL - 558
JO - Cancer Letters
JF - Cancer Letters
M1 - 216094
ER -