Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization

B.A. Mooso, R.L. Vinall, C.G. Tepper, R.M. Savoy, J.P. Cheung, S. Singh, S. Siddiqui, Y. Wang, R.G. Bedolla, A. Martinez, M. Mudryj, H.-J. Kung, R.W. DeVere White, P.M. Ghosh

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

As prostate cancer (CaP) is regulated by androgen receptor (AR) activity, metastatic CaP is treated with androgen deprivation therapy (ADT). Despite initial response, patients on ADT eventually progress to castration-resistant CaP (CRPC), which is currently incurable. We previously showed that cleavage of the 280 kDa structural protein Filamin A (FlnA) to a 90 kDa fragment, and nuclear localization of the cleaved product, sensitized CRPC cells to ADT. Hence, treatment promoting FlnA nuclear localization would enhance androgen responsiveness. Here, we show that FlnA nuclear localization induced apoptosis in CRPC cells during ADT, identifying it as a treatment tool in advanced CaP. Significantly, the natural product genistein combined polysaccharide (GCP) had a similar effect. Investigation of the mechanism of GCP-induced apoptosis showed that GCP induced FlnA cleavage and nuclear localization and that apoptosis resulting from GCP treatment was mediated by FlnA nuclear localization. Two main components of GCP are genistein and daidzein: the ability of GCP to induce G2 arrest was due to genistein whereas sensitivity to ADT stemmed from daidzein; hence, both were needed to mediate GCP's effects. FlnA cleavage is regulated by its phosphorylation; we show that ADT enhanced FlnA phosphorylation, which prevented its cleavage, whereas GCP inhibited FlnA phosphorylation, thereby sensitizing CaP cells to ADT. In a mouse model of CaP recurrence, GCP, but not vehicle, impeded relapse following castration, indicating that GCP, when administered with ADT, interrupted the development of CRPC. These results demonstrate the efficacy of GCP in promoting FlnA nuclear localization and enhancing androgen responsiveness in CaP. © 2012 Society for Endocrinology.
Original languageEnglish
Pages (from-to)759-777
Number of pages19
JournalEndocrine-Related Cancer
Volume19
Issue number6
DOIs
Publication statusPublished - Dec 2012
Externally publishedYes

Fingerprint

Filamins
Androgens
Prostatic Neoplasms
Therapeutics
Genistein
Castration
Phosphorylation
Apoptosis
genistein combined polysaccharide
Recurrence
Endocrinology
Androgen Receptors
Biological Products

Keywords

  • daidzein
  • filamin A
  • genistein
  • polysaccharide
  • advanced cancer
  • androgen deprivation therapy
  • animal experiment
  • animal model
  • apoptosis
  • article
  • cancer recurrence
  • castration
  • cell cycle arrest
  • controlled study
  • human
  • human cell
  • male
  • mouse
  • nonhuman
  • prostate cancer
  • protein phosphorylation
  • tumor xenograft
  • Androgen Antagonists
  • Androgens
  • Anilides
  • Animals
  • Apoptosis
  • Castration
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Nucleus
  • Filamins
  • Genistein
  • Male
  • Mice
  • Mice, Nude
  • Nitriles
  • Polysaccharides
  • Prostatic Neoplasms
  • Tosyl Compounds
  • Tumor Burden

Cite this

Mooso, B. A., Vinall, R. L., Tepper, C. G., Savoy, R. M., Cheung, J. P., Singh, S., ... Ghosh, P. M. (2012). Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization. Endocrine-Related Cancer, 19(6), 759-777. https://doi.org/10.1530/ERC-12-0171

Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization. / Mooso, B.A.; Vinall, R.L.; Tepper, C.G.; Savoy, R.M.; Cheung, J.P.; Singh, S.; Siddiqui, S.; Wang, Y.; Bedolla, R.G.; Martinez, A.; Mudryj, M.; Kung, H.-J.; DeVere White, R.W.; Ghosh, P.M.

In: Endocrine-Related Cancer, Vol. 19, No. 6, 12.2012, p. 759-777.

Research output: Contribution to journalArticle

Mooso, BA, Vinall, RL, Tepper, CG, Savoy, RM, Cheung, JP, Singh, S, Siddiqui, S, Wang, Y, Bedolla, RG, Martinez, A, Mudryj, M, Kung, H-J, DeVere White, RW & Ghosh, PM 2012, 'Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization', Endocrine-Related Cancer, vol. 19, no. 6, pp. 759-777. https://doi.org/10.1530/ERC-12-0171
Mooso, B.A. ; Vinall, R.L. ; Tepper, C.G. ; Savoy, R.M. ; Cheung, J.P. ; Singh, S. ; Siddiqui, S. ; Wang, Y. ; Bedolla, R.G. ; Martinez, A. ; Mudryj, M. ; Kung, H.-J. ; DeVere White, R.W. ; Ghosh, P.M. / Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization. In: Endocrine-Related Cancer. 2012 ; Vol. 19, No. 6. pp. 759-777.
@article{8f3529d608644ded88d6978bf0a4a710,
title = "Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization",
abstract = "As prostate cancer (CaP) is regulated by androgen receptor (AR) activity, metastatic CaP is treated with androgen deprivation therapy (ADT). Despite initial response, patients on ADT eventually progress to castration-resistant CaP (CRPC), which is currently incurable. We previously showed that cleavage of the 280 kDa structural protein Filamin A (FlnA) to a 90 kDa fragment, and nuclear localization of the cleaved product, sensitized CRPC cells to ADT. Hence, treatment promoting FlnA nuclear localization would enhance androgen responsiveness. Here, we show that FlnA nuclear localization induced apoptosis in CRPC cells during ADT, identifying it as a treatment tool in advanced CaP. Significantly, the natural product genistein combined polysaccharide (GCP) had a similar effect. Investigation of the mechanism of GCP-induced apoptosis showed that GCP induced FlnA cleavage and nuclear localization and that apoptosis resulting from GCP treatment was mediated by FlnA nuclear localization. Two main components of GCP are genistein and daidzein: the ability of GCP to induce G2 arrest was due to genistein whereas sensitivity to ADT stemmed from daidzein; hence, both were needed to mediate GCP's effects. FlnA cleavage is regulated by its phosphorylation; we show that ADT enhanced FlnA phosphorylation, which prevented its cleavage, whereas GCP inhibited FlnA phosphorylation, thereby sensitizing CaP cells to ADT. In a mouse model of CaP recurrence, GCP, but not vehicle, impeded relapse following castration, indicating that GCP, when administered with ADT, interrupted the development of CRPC. These results demonstrate the efficacy of GCP in promoting FlnA nuclear localization and enhancing androgen responsiveness in CaP. {\circledC} 2012 Society for Endocrinology.",
keywords = "daidzein, filamin A, genistein, polysaccharide, advanced cancer, androgen deprivation therapy, animal experiment, animal model, apoptosis, article, cancer recurrence, castration, cell cycle arrest, controlled study, human, human cell, male, mouse, nonhuman, prostate cancer, protein phosphorylation, tumor xenograft, Androgen Antagonists, Androgens, Anilides, Animals, Apoptosis, Castration, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Nucleus, Filamins, Genistein, Male, Mice, Mice, Nude, Nitriles, Polysaccharides, Prostatic Neoplasms, Tosyl Compounds, Tumor Burden",
author = "B.A. Mooso and R.L. Vinall and C.G. Tepper and R.M. Savoy and J.P. Cheung and S. Singh and S. Siddiqui and Y. Wang and R.G. Bedolla and A. Martinez and M. Mudryj and H.-J. Kung and {DeVere White}, R.W. and P.M. Ghosh",
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Xu, Y., Bismar, T.A., Su, J., Xu, B., Kristiansen, G., Varga, Z., Teng, L., Kumar, R., Filamin A regulates focal adhesion disassembly and suppresses breast cancer cell migration and invasion (2010) Journal of Experimental Medicine, 207, pp. 2421-2437. , doi:10.1084/jem.20100433; Zhang, Y., Zhong, S., Dong, Z., Chen, N., Bode, A.M., Ma, W., UVA induces Ser381 phosphorylation of p90RSK/MAPKAP-K1 via ERK and JNK pathways (2001) Journal of Biological Chemistry, 276, pp. 14572-14580. , doi:10.1074/jbc.M004615200; Zhang, Y., Zhu, G., Gu, S., Chen, X., Hu, H., Weng, S., Genistein inhibits osteolytic bone metastasis and enhances bone mineral in nude mice (2010) Environmental Toxicology and Pharmacology, 30, pp. 37-44. , doi:10.1016/j.etap.2010.03.016; Zhao, R., Xiang, N., Domann, F.E., Zhong, W., Effects of selenite and genistein on G2/M cell cycle arrest and apoptosis in human prostate cancer cells (2009) Nutrition and Cancer, 61, pp. 397-407. , doi:10.1080/01635580802582751",
year = "2012",
month = "12",
doi = "10.1530/ERC-12-0171",
language = "English",
volume = "19",
pages = "759--777",
journal = "Endocrine-Related Cancer",
issn = "1351-0088",
publisher = "Society for Endocrinology",
number = "6",

}

TY - JOUR

T1 - Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization

AU - Mooso, B.A.

AU - Vinall, R.L.

AU - Tepper, C.G.

AU - Savoy, R.M.

AU - Cheung, J.P.

AU - Singh, S.

AU - Siddiqui, S.

AU - Wang, Y.

AU - Bedolla, R.G.

AU - Martinez, A.

AU - Mudryj, M.

AU - Kung, H.-J.

AU - DeVere White, R.W.

AU - Ghosh, P.M.

N1 - 引用次數:13 Export Date: 5 March 2018 CODEN: ERCAE 通訊地址: Ghosh, P.M.; Department of Urology, University of California Davis School of Medicine, 4860 Y Street, Sacramento, CA 95817, United States; 電子郵件: paramita.ghosh@ucdmc.ucdavis.edu 化學物質/CAS: daidzein, 486-66-8; genistein, 446-72-0; Androgen Antagonists; Androgens; Anilides; Filamins; FlnA protein, mouse; Genistein, DH2M523P0H; Nitriles; Polysaccharides; Tosyl Compounds; bicalutamide, 90357-06-5; genistein combined polysaccharide 參考文獻: Aggarwal, B.B., Shishodia, S., Molecular targets of dietary agents for prevention and therapy of cancer (2006) Biochemical Pharmacology, 71, pp. 1397-1421. , doi:10.1016/j.bcp.2006.02.009; Agus, D.B., Cordon-Cardo, C., Fox, W., Drobnjak, M., Koff, A., Golde, D.W., Scher, H.I., Prostate cancer cell cycle regulators: Response to androgen withdrawal and development of androgen independence (1999) Journal of the National Cancer Institute, 91, pp. 1869-1876. , doi:10.1093/jnci/91.21.1869; Agus, D.B., Akita, R.W., Fox, W.D., Lewis, G.D., Higgins, B., Pisacane, P.I., Lofgren, J.A., Maiese, K., Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth (2002) Cancer Cell, 2, pp. 127-137. , doi:10.1016/S1535-6108(02)00097-1; 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Xu, Y., Bismar, T.A., Su, J., Xu, B., Kristiansen, G., Varga, Z., Teng, L., Kumar, R., Filamin A regulates focal adhesion disassembly and suppresses breast cancer cell migration and invasion (2010) Journal of Experimental Medicine, 207, pp. 2421-2437. , doi:10.1084/jem.20100433; Zhang, Y., Zhong, S., Dong, Z., Chen, N., Bode, A.M., Ma, W., UVA induces Ser381 phosphorylation of p90RSK/MAPKAP-K1 via ERK and JNK pathways (2001) Journal of Biological Chemistry, 276, pp. 14572-14580. , doi:10.1074/jbc.M004615200; Zhang, Y., Zhu, G., Gu, S., Chen, X., Hu, H., Weng, S., Genistein inhibits osteolytic bone metastasis and enhances bone mineral in nude mice (2010) Environmental Toxicology and Pharmacology, 30, pp. 37-44. , doi:10.1016/j.etap.2010.03.016; Zhao, R., Xiang, N., Domann, F.E., Zhong, W., Effects of selenite and genistein on G2/M cell cycle arrest and apoptosis in human prostate cancer cells (2009) Nutrition and Cancer, 61, pp. 397-407. , doi:10.1080/01635580802582751

PY - 2012/12

Y1 - 2012/12

N2 - As prostate cancer (CaP) is regulated by androgen receptor (AR) activity, metastatic CaP is treated with androgen deprivation therapy (ADT). Despite initial response, patients on ADT eventually progress to castration-resistant CaP (CRPC), which is currently incurable. We previously showed that cleavage of the 280 kDa structural protein Filamin A (FlnA) to a 90 kDa fragment, and nuclear localization of the cleaved product, sensitized CRPC cells to ADT. Hence, treatment promoting FlnA nuclear localization would enhance androgen responsiveness. Here, we show that FlnA nuclear localization induced apoptosis in CRPC cells during ADT, identifying it as a treatment tool in advanced CaP. Significantly, the natural product genistein combined polysaccharide (GCP) had a similar effect. Investigation of the mechanism of GCP-induced apoptosis showed that GCP induced FlnA cleavage and nuclear localization and that apoptosis resulting from GCP treatment was mediated by FlnA nuclear localization. Two main components of GCP are genistein and daidzein: the ability of GCP to induce G2 arrest was due to genistein whereas sensitivity to ADT stemmed from daidzein; hence, both were needed to mediate GCP's effects. FlnA cleavage is regulated by its phosphorylation; we show that ADT enhanced FlnA phosphorylation, which prevented its cleavage, whereas GCP inhibited FlnA phosphorylation, thereby sensitizing CaP cells to ADT. In a mouse model of CaP recurrence, GCP, but not vehicle, impeded relapse following castration, indicating that GCP, when administered with ADT, interrupted the development of CRPC. These results demonstrate the efficacy of GCP in promoting FlnA nuclear localization and enhancing androgen responsiveness in CaP. © 2012 Society for Endocrinology.

AB - As prostate cancer (CaP) is regulated by androgen receptor (AR) activity, metastatic CaP is treated with androgen deprivation therapy (ADT). Despite initial response, patients on ADT eventually progress to castration-resistant CaP (CRPC), which is currently incurable. We previously showed that cleavage of the 280 kDa structural protein Filamin A (FlnA) to a 90 kDa fragment, and nuclear localization of the cleaved product, sensitized CRPC cells to ADT. Hence, treatment promoting FlnA nuclear localization would enhance androgen responsiveness. Here, we show that FlnA nuclear localization induced apoptosis in CRPC cells during ADT, identifying it as a treatment tool in advanced CaP. Significantly, the natural product genistein combined polysaccharide (GCP) had a similar effect. Investigation of the mechanism of GCP-induced apoptosis showed that GCP induced FlnA cleavage and nuclear localization and that apoptosis resulting from GCP treatment was mediated by FlnA nuclear localization. Two main components of GCP are genistein and daidzein: the ability of GCP to induce G2 arrest was due to genistein whereas sensitivity to ADT stemmed from daidzein; hence, both were needed to mediate GCP's effects. FlnA cleavage is regulated by its phosphorylation; we show that ADT enhanced FlnA phosphorylation, which prevented its cleavage, whereas GCP inhibited FlnA phosphorylation, thereby sensitizing CaP cells to ADT. In a mouse model of CaP recurrence, GCP, but not vehicle, impeded relapse following castration, indicating that GCP, when administered with ADT, interrupted the development of CRPC. These results demonstrate the efficacy of GCP in promoting FlnA nuclear localization and enhancing androgen responsiveness in CaP. © 2012 Society for Endocrinology.

KW - daidzein

KW - filamin A

KW - genistein

KW - polysaccharide

KW - advanced cancer

KW - androgen deprivation therapy

KW - animal experiment

KW - animal model

KW - apoptosis

KW - article

KW - cancer recurrence

KW - castration

KW - cell cycle arrest

KW - controlled study

KW - human

KW - human cell

KW - male

KW - mouse

KW - nonhuman

KW - prostate cancer

KW - protein phosphorylation

KW - tumor xenograft

KW - Androgen Antagonists

KW - Androgens

KW - Anilides

KW - Animals

KW - Apoptosis

KW - Castration

KW - Cell Cycle Checkpoints

KW - Cell Line, Tumor

KW - Cell Nucleus

KW - Filamins

KW - Genistein

KW - Male

KW - Mice

KW - Mice, Nude

KW - Nitriles

KW - Polysaccharides

KW - Prostatic Neoplasms

KW - Tosyl Compounds

KW - Tumor Burden

U2 - 10.1530/ERC-12-0171

DO - 10.1530/ERC-12-0171

M3 - Article

VL - 19

SP - 759

EP - 777

JO - Endocrine-Related Cancer

JF - Endocrine-Related Cancer

SN - 1351-0088

IS - 6

ER -