Galbanic acid decreases androgen receptor abundance and signaling and induces G 1 arrest in prostate cancer cells

Yong Zhang, Kwan Hyun Kim, Wei Zhang, Yinglu Guo, Sung Hoon Kim, Junxuan Lu

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4-2 vs. AR(-) DU145 and PC-3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb Ferula assafoetida and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(-) PCa cells. GBA induced a caspase-mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA downregulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR-dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide (Bic), LNCaP cell culture assays did not detect agonist activity of GBA. GBA and Bic exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G 1 arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D 1 without the causal involvement of cyclin-dependent kinase (CDK) inhibitory proteins P21 Cip1 and P27 Kip1. In summary, the novelty of GBA as an anti-AR compound resides in the distinction between GBA and Bic with respect to AR protein turnover and a lack of agonist effect. Our observations of anti-AR and cell cycle arrest actions plus the anti-angiogenesis effect reported elsewhere suggest GBA as a multitargeting drug candidate for the prevention and therapy of PCa.

Original languageEnglish (US)
Pages (from-to)200-212
Number of pages13
JournalInternational Journal of Cancer
Volume130
Issue number1
DOIs
StatePublished - Jan 11 2012

Fingerprint

Androgen Receptors
Prostatic Neoplasms
galbanic acid
Ferula
Growth
Androgen Receptor Antagonists
Cyclin D
Cyclins
Caspase Inhibitors
Angiogenesis Inhibitors
Cyclin-Dependent Kinases
Medicinal Plants
Caspases
Cell Cycle Checkpoints
Pharmaceutical Preparations
Cell Cycle
Proteins
Down-Regulation
Cell Culture Techniques

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Zhang, Yong ; Kim, Kwan Hyun ; Zhang, Wei ; Guo, Yinglu ; Kim, Sung Hoon ; Lu, Junxuan. / Galbanic acid decreases androgen receptor abundance and signaling and induces G 1 arrest in prostate cancer cells. In: International Journal of Cancer. 2012 ; Vol. 130, No. 1. pp. 200-212.
@article{dbd8e31efc4e4e4e81399049b28c3b20,
title = "Galbanic acid decreases androgen receptor abundance and signaling and induces G 1 arrest in prostate cancer cells",
abstract = "Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4-2 vs. AR(-) DU145 and PC-3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb Ferula assafoetida and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(-) PCa cells. GBA induced a caspase-mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA downregulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR-dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide (Bic), LNCaP cell culture assays did not detect agonist activity of GBA. GBA and Bic exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G 1 arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D 1 without the causal involvement of cyclin-dependent kinase (CDK) inhibitory proteins P21 Cip1 and P27 Kip1. In summary, the novelty of GBA as an anti-AR compound resides in the distinction between GBA and Bic with respect to AR protein turnover and a lack of agonist effect. Our observations of anti-AR and cell cycle arrest actions plus the anti-angiogenesis effect reported elsewhere suggest GBA as a multitargeting drug candidate for the prevention and therapy of PCa.",
author = "Yong Zhang and Kim, {Kwan Hyun} and Wei Zhang and Yinglu Guo and Kim, {Sung Hoon} and Junxuan Lu",
year = "2012",
month = "1",
day = "11",
doi = "10.1002/ijc.25993",
language = "English (US)",
volume = "130",
pages = "200--212",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "1",

}

Galbanic acid decreases androgen receptor abundance and signaling and induces G 1 arrest in prostate cancer cells. / Zhang, Yong; Kim, Kwan Hyun; Zhang, Wei; Guo, Yinglu; Kim, Sung Hoon; Lu, Junxuan.

In: International Journal of Cancer, Vol. 130, No. 1, 11.01.2012, p. 200-212.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Galbanic acid decreases androgen receptor abundance and signaling and induces G 1 arrest in prostate cancer cells

AU - Zhang, Yong

AU - Kim, Kwan Hyun

AU - Zhang, Wei

AU - Guo, Yinglu

AU - Kim, Sung Hoon

AU - Lu, Junxuan

PY - 2012/1/11

Y1 - 2012/1/11

N2 - Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4-2 vs. AR(-) DU145 and PC-3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb Ferula assafoetida and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(-) PCa cells. GBA induced a caspase-mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA downregulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR-dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide (Bic), LNCaP cell culture assays did not detect agonist activity of GBA. GBA and Bic exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G 1 arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D 1 without the causal involvement of cyclin-dependent kinase (CDK) inhibitory proteins P21 Cip1 and P27 Kip1. In summary, the novelty of GBA as an anti-AR compound resides in the distinction between GBA and Bic with respect to AR protein turnover and a lack of agonist effect. Our observations of anti-AR and cell cycle arrest actions plus the anti-angiogenesis effect reported elsewhere suggest GBA as a multitargeting drug candidate for the prevention and therapy of PCa.

AB - Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4-2 vs. AR(-) DU145 and PC-3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb Ferula assafoetida and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(-) PCa cells. GBA induced a caspase-mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA downregulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR-dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide (Bic), LNCaP cell culture assays did not detect agonist activity of GBA. GBA and Bic exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G 1 arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D 1 without the causal involvement of cyclin-dependent kinase (CDK) inhibitory proteins P21 Cip1 and P27 Kip1. In summary, the novelty of GBA as an anti-AR compound resides in the distinction between GBA and Bic with respect to AR protein turnover and a lack of agonist effect. Our observations of anti-AR and cell cycle arrest actions plus the anti-angiogenesis effect reported elsewhere suggest GBA as a multitargeting drug candidate for the prevention and therapy of PCa.

UR - http://www.scopus.com/inward/record.url?scp=80255123491&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80255123491&partnerID=8YFLogxK

U2 - 10.1002/ijc.25993

DO - 10.1002/ijc.25993

M3 - Article

C2 - 21328348

AN - SCOPUS:80255123491

VL - 130

SP - 200

EP - 212

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 1

ER -