title: Novel membrane-associated androgen receptor splice variant potentiates proliferative and survival responses in prostate cancer cells.
abstract: Progression from the androgen-sensitive to androgen-insensitive (or castration-resistant) stage is the major obstacle for sustained effectiveness of hormonal therapy for prostate cancer. The androgen receptor (AR) and its splice variants play important roles in regulating the transcription program essential for castration resistance. Here, we report the identification of a novel AR splice variant, designated as AR8, which is up-regulated in castration-resistant prostate cancer cells. AR8 is structurally different from other known AR splice variants because it lacks a DNA binding domain and therefore, unlikely functions as a transcription factor on its own. Immunofluorescence staining revealed that AR8 was primarily localized on the plasma membrane, possibly through palmitoylation of two cysteine residues within its unique C-terminal sequence. Mutation of these putative palmitoylation sites in AR8 led to loss of its plasma membrane localization. In addition, we demonstrated that overexpression of AR8 in prostate cancer cells promoted association of Src and AR with the EGF receptor in response to EGF treatment and enhanced tyrosine phosphorylation of AR. Conversely, specific knockdown of AR8 expression in prostate cancer cells compromised EGF-induced Src activation and AR phosphorylation. This effect was accompanied with attenuation of proliferation and increased apoptosis in prostate cancer cells cultured in androgen-depleted medium. We also showed that AR8 was required for optimal transcriptional activity of AR in response to treatment of both androgen and EGF. Taken together, our results demonstrate that the membrane-associated AR8 isoform may contribute to castration resistance by potentiating AR-mediated proliferative and survival responses to hormones and growth factors.
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: Xi
authors: X
authors: Yang
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: Zhiyong
authors: Z
authors: Guo
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: Feng
authors: F
authors: Sun
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: Wei
authors: W
authors: Li
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: Alan
authors: A
authors: Alfano
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: Hermela
authors: H
authors: Shimelis
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: Mingyuan
authors: M
authors: Chen
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: Angela M H
authors: AMH
authors: Brodie
authors: Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: Hegang
authors: H
authors: Chen
authors: Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702.
authors: Zhen
authors: Z
authors: Xiao
authors: Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702.
authors: Timothy D
authors: TD
authors: Veenstra
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201. Electronic address: yqiu@som.umaryland.edu.
authors: Yun
authors: Y
authors: Qiu
mesh_terms: D017398:Alternative Splicing; D019943:Amino Acid Substitution; D000728:Androgens / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002522:Chlorocebus aethiops; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D054878:Lipoylation; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000728:Androgens; D009363:Neoplasm Proteins; D011944:Receptors, Androgen; D004815:Epidermal Growth Factor; D019061:src-Family Kinases