Protein kinase D inhibitor CRT0066101 suppresses bladder cancer growth in vitro and xenografts via blockade of the cell cycle at G2/M.

Cellular and Molecular Life Sciences : CMLS
Q Quentin LiPiyush K Agarwal

Abstract

The protein kinase D (PKD) family of proteins are important regulators of tumor growth, development, and progression. CRT0066101, an inhibitor of PKD, has antitumor activity in multiple types of carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer are not understood. In the present study, we show that CRT0066101 suppressed the proliferation and migration of four bladder cancer cell lines in vitro. We also demonstrate that CRT0066101 blocked tumor growth in a mouse flank xenograft model of bladder cancer. To further assess the role of PKD in bladder carcinoma, we examined the three PKD isoforms and found that PKD2 was highly expressed in eight bladder cancer cell lines and in urothelial carcinoma tissues from the TCGA database, and that short hairpin RNA (shRNA)-mediated knockdown of PKD2 dramatically reduced bladder cancer growth and invasion in vitro and in vivo, suggesting that the effect of the compound in bladder cancer is mediated through inhibition of PKD2. This notion was corroborated by demonstrating that the levels of phospho-PKD2 were markedly decreased in CRT0066101-treated bladder tumor explants. Furthermore, our cell cycle analysis by flow cytometry revealed that CRT0066101 treatment or PKD...Continue Reading

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Citations

Jan 17, 2020·Journal of Cellular and Molecular Medicine·Yan LiuLiming Chen
Sep 16, 2020·Obesity Reviews : an Official Journal of the International Association for the Study of Obesity·Mark C RentonKirsten F Howlett
Jul 18, 2019·Molecular Cancer Research : MCR·Ilige Youssef, Jean-Marc Ricort
Jul 19, 2018·Molecular Cancer Research : MCR·Adhiraj RoyQiming Jane Wang
Feb 22, 2021·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Lei YuXiaoPo Zhang
Apr 9, 2021·ChemMedChem·Philippe GillesWim M De Borggraeve
May 6, 2021·EMBO Molecular Medicine·Jonathan Trujillo-VieraGrzegorz Sumara

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Methods Mentioned

BETA
Assay
electrophoresis
xenograft
biopsies
transfection
RNA-Seq
PMA
Antibody Array
gene knockdown
flow cytometry

Software Mentioned

GraphPad Prism
R
limma R package
SPSS
FlowJo
GraphPad
Celigo

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