title: Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties.
abstract: Advanced prostate adenocarcinomas enriched in stem-cell features, as well as variant androgen receptor (AR)-negative neuroendocrine (NE)/small-cell prostate cancers are difficult to treat, and account for up to 30% of prostate cancer-related deaths every year. While existing therapies for prostate cancer such as androgen deprivation therapy (ADT), destroy the bulk of the AR-positive cells within the tumor, eradicating this population eventually leads to castration-resistance, owing to the continued survival of AR-/lostem-like cells. In this study, we identified a critical nexus between p38MAPK signaling, and the transcription factor Forkhead Box Protein C2 (FOXC2) known to promote cancer stem-cells and metastasis. We demonstrate that prostate cancer cells that are insensitive to ADT, as well as high-grade/NE prostate tumors, are characterized by elevated FOXC2, and that targeting FOXC2 using a well-tolerated p38 inhibitor restores epithelial attributes and ADT-sensitivity, and reduces the shedding of circulating tumor cells in vivo with significant shrinkage in the tumor mass. This study thus specifies a tangible mechanism to target the AR-/lopopulation of prostate cancer cells with stem-cell properties.
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A N
authors.initials: AN
authors.lastname: Paranjape
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Soundararajan
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Werden
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Joseph
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Taube
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Rodriguez-Canales
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sphyris
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: I
authors.initials: I
authors.lastname: Wistuba
authors.affiliation: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Miura
authors.affiliation: Department of Oncological Sciences, Moffitt Cancer Center, University of South Florida, Tampa, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Dhillon
authors.affiliation: Department of Oncological Sciences, Moffitt Cancer Center, University of South Florida, Tampa, FL, USA.
authors.forename: N
authors.initials: N
authors.lastname: Mahajan
authors.affiliation: Department of Oncological Sciences, Moffitt Cancer Center, University of South Florida, Tampa, FL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mahajan
authors.affiliation: Department of Integrative Biology and Pharmacology, School of Medicine, School of Biomedical Informatics, UT Health Sciences Center at Houston, Houston, TX, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ittmann
authors.affiliation: Department of Genitourinary Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Maity
authors.affiliation: Department of Genitourinary Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Logothetis
authors.affiliation: Department of Molecular Carcinogenesis, Science Park, UT MD Anderson Cancer Center, Smithville, TX, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Tang
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX, USA.|Metastasis Research Center, UT MD Anderson Cancer Center, Houston, TX, USA.|Center for Stem Cell and Developmental Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Mani
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008954:Models, Biological; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D009570:Nitriles; D010641:Phenotype; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D012008:Recurrence; D023041:Xenograft Model Antitumor Assays; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism
chemical_list: D000728:Androgens; D001549:Benzamides; D051858:Forkhead Transcription Factors; D009570:Nitriles; D011944:Receptors, Androgen; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C082078:mesenchyme fork head 1 protein; D010669:Phenylthiohydantoin; C540278:enzalutamide; D017430:Prostate-Specific Antigen