Title of Article |
Targeted Modulation of FAK/PI3K/PDK1/AKT and FAK/p53 Pathways by Cucurbitacin B for the Antiproliferation Effect Against Human Cholangiocarcinoma Cells |
Date of Acceptance |
17 June 2020 |
Journal |
Title of Journal |
The American Journal of Chinese Medicine |
Standard |
SCOPUS |
Institute of Journal |
World Scientific Publishing Co. Pte. Ltd. |
ISBN/ISSN |
1793-6853 (online), 0192-415X (print) |
Volume |
48 |
Issue |
6 |
Month |
September |
Year of Publication |
2020 |
Page |
|
Abstract |
Inadequate responses to traditional chemotherapeutic agents in cholangiocarcinoma
(CCA) emphasize a requirement for new effective compounds for treatment of this malignancy.
The aim of this study was to investigate the antiproliferative property of cucurbitacin B on
KKU-100 CCA cells. The determination of underlying molecular mechanisms was also carried
out. The results revealed that cucurbitacin B suppressed growth and replicative ability to form
colonies of CCA cells, suggesting the antiproliferative effect of this compound against the cells.
Flow cytometry analysis demonstrated that the interfering effect of cucurbitacin B on the CCA
cell cycle at the G2/M phase was accountable for its antiproliferation property. Accompanied
with cell cycle disruption, cucurbitacin B altered the expression of proteins involved in the
G2/M phase transition including downregulation of cyclin A, cyclin D1 and cdc25A, and
upregulation of p21. Additional molecular studies demonstrated that cucurbitacin B suppressed
the activation of focal adhesion kinase (FAK) which consequently resulted in inhibition of its
kinase-dependent and kinase-independent downstream targets contributing to regulation of cell
proliferation including PI3K/ PDK1/ AKT and p53 proteins. In this study, the transient
knockdown of FAK using siRNA was employed to ascertain the role of FAK in CCA cell
proliferation. Finally, the effect of cucurbitacin B on upstream receptor tyrosine kinases
regulating FAK activation was elucidated. The results showed that the inhibitory effect of
cucurbitacin B on FAK activation in CCA cells is mediated via interference of EGFR and
HER2 expression. Collectively, cucurbitacin B might be a promising drug for CCA treatment
by targeting FAK protein.
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Keyword |
Cucurbitacin B; Cholangiocarcinoma; Antiproliferation; Focal adhesion kinase; p53; FAK pathway |
Author |
|
Reviewing Status |
มีผู้ประเมินอิสระ |
Status |
ได้รับการตอบรับให้ตีพิมพ์ |
Level of Publication |
นานาชาติ |
citation |
false |
Part of thesis |
true |
Attach file |
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Citation |
0
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