Publication: Inhibition of CSF1R and AKT by (±)-kusunokinin hinders breast cancer cell proliferation
Issued Date
2020-09-01
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ISSN
19506007
07533322
07533322
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2-s2.0-85086446158
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Mahidol University
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SCOPUS
Bibliographic Citation
Biomedicine and Pharmacotherapy. Vol.129, (2020)
Suggested Citation
Thidarath Rattanaburee, Varomyalin Tipmanee, Aman Tedasen, Tienthong Thongpanchang, Potchanapond Graidist Inhibition of CSF1R and AKT by (±)-kusunokinin hinders breast cancer cell proliferation. Biomedicine and Pharmacotherapy. Vol.129, (2020). doi:10.1016/j.biopha.2020.110361 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/58359
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Title
Inhibition of CSF1R and AKT by (±)-kusunokinin hinders breast cancer cell proliferation
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Abstract
© 2020 The Author(s) Kusunokinin, a lignan compound, inhibits cancer cell proliferation and induces apoptosis; however, the role of kusunokinin is not fully understood. Here, we aimed to identify a target protein of (−)-kusunokinin and determine the protein levels of its downstream molecules. We found that (−)-kusunokinin bound 5 possible target proteins, including CSF1R, MMP-12, HSP90-α, CyclinB1 and MEK1 with ΔGbind less than −10.40 kcal/mol. MD simulation indicated (−)-kusunokinin and pexidartinib (P31, a specific CSF1R binding compound) shared some extents of functional similarity in which (−)-kusunokinin bound CSF1R at the juxtamembrane (JM) region with aromatic amino acids similar to pexidartinib using π-π interaction, as well as hydrogen bond. Both P31 and (−)-kusunokinin moved into the same CSF1R region and W7 was a mutual key residue. However, the P31 binding site differed from the (−)-kusunokinin binding site. For in vitro study, the synthetic (±)-kusunokinin exhibited stronger cytotoxicity than picropodophyllotoxin, silibinin and etoposide on MCF-7 cells and represented less toxicity than picropodophyllotoxin and doxorubicin on L-929 and MCF-12A cells. Knocking down CSF1R using a specific siRNA combination with (±)-kusunokinin demonstrated levels of cell proliferation proteins slightly higher than siRNA-CSF1R treatment. However, siRNA-CSF1R combination with P31 represented the number of cell viability and cell proliferation proteins, like in the control groups (Lipofectamine and siRNA-Luciferase). Moreover, (±)-kusunokinin suppressed CSF1R and its downstream proteins, including AKT, CyclinD1 and CDK1. Meanwhile, both P31 and siRNA-CSF1R dramatically suppressed CSF1R, MEK1, AKT, ERK, CyclinB1, CyclinD1 and CDK1. Our overall results indicate that the mechanism of (±)-kusunokinin differed fairly from P31. We have concluded that (±)-kusunokinin inhibited breast cancer cell proliferation partially through the binding and suppression of CSF1R, which consequently affected AKT and its downstream molecules.