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

Hiroshi Hongo; Takeo Kosaka; Mototsugu Oya

doi:10.1111/cas.13729

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

Hiroshi Hongo, Takeo Kosaka, Mototsugu Oya

Department of Urology

Research output: Contribution to journal › Article › peer-review

25 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 language	English
Pages (from-to)	2937-2945
Number of pages	9
Journal	Cancer science
Volume	109
Issue number	9
DOIs	https://doi.org/10.1111/cas.13729
Publication status	Published - 2018 Sept

Keywords

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

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1111/cas.13729

Cite this

@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 = "ERK signaling, PI3K/AKT signaling, cabazitaxel resistance, castration-resistant prostate cancer (CRPC), cell cycle",

author = "Hiroshi Hongo and Takeo Kosaka and Mototsugu Oya",

note = "Funding Information: Yoko Suzuki and Yumiko Kito provided technical assistance. This study was supported in part by Grants-in-Aid for Scientific Research (#17K16813, #15K20109 to H. Hongo and #17K11158 to T. Kosaka) from The Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT). The study was supported in part by a Keio University Grant-in-Aid for Encouragement of Young Medical Scientists (02-002-0014, 02-002-0020 to H. Hongo) from Keio University School of Medicine. The study was supported in part by research grants to T. Kosaka from The Takeda Science Foundation, Japan and the Japan Research Foundation for Clinical Pharmacology. The study was also supported in part by a research grant from the MEXT-Supported Program for the Strategic Research Foundation at Private Universities. Publisher Copyright: {\textcopyright} 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.",

year = "2018",

month = sep,

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

N1 - Funding Information: Yoko Suzuki and Yumiko Kito provided technical assistance. This study was supported in part by Grants-in-Aid for Scientific Research (#17K16813, #15K20109 to H. Hongo and #17K11158 to T. Kosaka) from The Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT). The study was supported in part by a Keio University Grant-in-Aid for Encouragement of Young Medical Scientists (02-002-0014, 02-002-0020 to H. Hongo) from Keio University School of Medicine. The study was supported in part by research grants to T. Kosaka from The Takeda Science Foundation, Japan and the Japan Research Foundation for Clinical Pharmacology. The study was also supported in part by a research grant from the MEXT-Supported Program for the Strategic Research Foundation at Private Universities. Publisher Copyright: © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

PY - 2018/9

Y1 - 2018/9

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 - ERK signaling

KW - PI3K/AKT signaling

KW - cabazitaxel resistance

KW - castration-resistant prostate cancer (CRPC)

KW - cell cycle

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

C2 - 29989268

AN - SCOPUS:85052506126

SN - 1347-9032

VL - 109

SP - 2937

EP - 2945

JO - Cancer Science

JF - Cancer Science

IS - 9

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this