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Cancer Sci. 2018 Jul 10. doi: 10.1111/cas.13729. [Epub ahead of print]

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

Author information

1
Keio University School of Medicine, Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, 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 about 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 extracellular signal-regulated kinase (ERK) signaling was detected in DU145CR. DU145CR 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 had enhancement of phosphoinositide 3-kinase (PI3K)/AKT signaling. PI3K/mTOR inhibitor NVP-BEZ 235 had a significant anti-tumor effect in PC3CR. CBZ-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 may be therapeutic targets for CBZ-resistant CRPC. This article is protected by copyright. All rights reserved.

KEYWORDS:

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

PMID:
29989268
DOI:
10.1111/cas.13729
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