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

Hiroshi Hongo, Takeo Kosaka, Mototsugu Oya

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2937-2945
Number of pages9
JournalCancer Science
Volume109
Issue number9
DOIs
Publication statusPublished - 2018 Sep 1

Fingerprint

Castration
Prostatic Neoplasms
Phosphatidylinositol 3-Kinases
docetaxel
Cell Line
Cell Cycle
cabazitaxel
Cell Nucleus Division
Mitogen-Activated Protein Kinase Kinases
Multigene Family
Transcriptome
Cell Division
Flow Cytometry
Cell Proliferation

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Analysis of cabazitaxel-resistant mechanism in human castration-resistant prostate cancer. / Hongo, Hiroshi; Kosaka, Takeo; Oya, Mototsugu.

In: Cancer Science, Vol. 109, No. 9, 01.09.2018, p. 2937-2945.

Research output: Contribution to journalArticle

@article{045d6266f5044094b48625d97be804b9,
title = "Analysis of cabazitaxel-resistant mechanism in human castration-resistant prostate cancer",
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 = "cabazitaxel resistance, castration-resistant prostate cancer (CRPC), cell cycle, ERK signaling, PI3K/AKT signaling",
author = "Hiroshi Hongo and Takeo Kosaka and Mototsugu Oya",
year = "2018",
month = "9",
day = "1",
doi = "10.1111/cas.13729",
language = "English",
volume = "109",
pages = "2937--2945",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "9",

}

TY - JOUR

T1 - Analysis of cabazitaxel-resistant mechanism in human castration-resistant prostate cancer

AU - Hongo, Hiroshi

AU - Kosaka, Takeo

AU - Oya, Mototsugu

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

KW - cabazitaxel resistance

KW - castration-resistant prostate cancer (CRPC)

KW - cell cycle

KW - ERK signaling

KW - PI3K/AKT signaling

UR - http://www.scopus.com/inward/record.url?scp=85052506126&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052506126&partnerID=8YFLogxK

U2 - 10.1111/cas.13729

DO - 10.1111/cas.13729

M3 - Article

VL - 109

SP - 2937

EP - 2945

JO - Cancer Science

JF - Cancer Science

SN - 1347-9032

IS - 9

ER -