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.
authors.affiliation: VA Northern California Health Care System, Mather, California, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Mooso
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Vinall
authors.forename: Clifford G
authors.initials: CG
authors.lastname: Tepper
authors.forename: Rosalinda M
authors.initials: RM
authors.lastname: Savoy
authors.forename: Jean P
authors.initials: JP
authors.lastname: Cheung
authors.forename: Sheetal
authors.initials: S
authors.lastname: Singh
authors.forename: Salma
authors.initials: S
authors.lastname: Siddiqui
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Roble G
authors.initials: RG
authors.lastname: Bedolla
authors.forename: Anthony
authors.initials: A
authors.lastname: Martinez
authors.forename: Maria
authors.initials: M
authors.lastname: Mudryj
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.forename: Ralph W
authors.initials: RW
authors.lastname: Devere White
authors.forename: Paramita M
authors.initials: PM
authors.lastname: Ghosh
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002369:Castration; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D064448:Filamins / Q000378:metabolism*; D019833:Genistein / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000494:pharmacology; D011134:Polysaccharides / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014105:Tosyl Compounds / Q000494:pharmacology; D047368:Tumor Burden
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D064448:Filamins; C529499:FlnA protein, mouse; D009570:Nitriles; D011134:Polysaccharides; D014105:Tosyl Compounds; C473311:genistein combined polysaccharide; C053541:bicalutamide; D019833:Genistein