Format

Send to

Choose Destination
Cancer Sci. 2018 Sep;109(9):2937-2945. doi: 10.1111/cas.13729. Epub 2018 Aug 6.

Analysis of cabazitaxel-resistant mechanism in human castration-resistant prostate cancer.

Author information

1
Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Abstract

Cabazitaxel (CBZ) is approved for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, efficacy of CBZ for CRPC is limited and there are no effective treatments for CBZ-resistant CRPC. In order to investigate the CBZ-resistant mechanism, the establishment of a CBZ-resistant cell line is urgently needed. We established CBZ-resistant CRPC cell lines DU145CR and PC3CR by incubating DU145 and PC3 cells with gradually increasing concentrations of CBZ for approximately 2 years. We analyzed the gene expression profiles and cell cycle changes using microarray and flow cytometry. Pathway analysis revealed DU145CR cells had enhanced gene clusters of cell division and mitotic nuclear division. Enhancement of ERK signaling was detected in DU145CR cells. DU145CR cells had resistance to G2 /M arrest induced by CBZ through ERK signaling activation. The MEK inhibitor PD184352 significantly inhibited cell proliferation of DU145CR. In contrast to DU145CR, PC3CR cells had enhancement of PI3K/AKT signaling. The PI3K/mTOR inhibitor NVP-BEZ 235 had a significant antitumor effect in PC3CR cells. Cabazitaxel -resistant CRPC cells established in our laboratory had enhancement of cell cycle progression signals and resistance to G2 /M arrest induced by CBZ. Enhancement of ERK signaling or PI3K/AKT signaling were detected in the cell lines, so ERK or PI3K/AKT could be therapeutic targets for CBZ-resistant CRPC.

KEYWORDS:

ERK signaling; PI3K/AKT signaling; cabazitaxel resistance; castration-resistant prostate cancer (CRPC); cell cycle

PMID:
29989268
PMCID:
PMC6125448
DOI:
10.1111/cas.13729
[Indexed for MEDLINE]
Free PMC Article

MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center