title: Tissue transglutaminase expression promotes castration-resistant phenotype and transcriptional repression of androgen receptor.
abstract: Many studies have supported a role for inflammation in prostate tumour growth. However, the contribution of inflammation to the development of castration-resistant prostate cancer remains largely unknown. Based on observations that aberrant expression of the proinflammatory protein tissue transglutaminase (TG2) is associated with development of drug resistance and metastatic phenotype in multiple cancer types, we determined TG2 expression in prostate cancer cells. Herein we report that human prostate cancer cell lines with low expression of androgen receptor (AR) had high basal levels of TG2 expression. Also, overexpression of TG2 negatively regulated AR mRNA and protein expression and attenuated androgen sensitivity of prostate cancer cells. TG2 expression in prostate cancer cells was associated with increased invasion and resistance to chemotherapy. Mechanistically, TG2 activated nuclear factor (NF)-κB and induced epithelial-mesenchymal transition. TG2/NF-κB-mediated decrease in AR expression resulted from transcriptional repression involving cis-interaction of NF-κB in a complex with TG2 with the 5'-untranslated region of AR. Negative regulation of AR could be partially abrogated by repression of TG2 or NF-κB (p65/RelA) by gene-specific small interfering RNA. These results suggested that a novel pathway links androgen dependence with TG2-regulated inflammatory signalling and hence may make TG2 a novel therapeutic target for the prevention and treatment of castration-resistant prostate cancer.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Amy Lee
authors.initials: AL
authors.lastname: Han
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Jansina Y
authors.initials: JY
authors.lastname: Fok
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Tyagi
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States. Electronic address: kmehta@mdanderson.org.
authors.forename: Kapil
authors.initials: K
authors.lastname: Mehta
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D064129:Prostatic Neoplasms, Castration-Resistant / Q000201:enzymology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D011944:Receptors, Androgen / Q000378:metabolism*; D014162:Transfection; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Androgen receptor; Castration-resistant prostate cancer; Inflammation; NF-κB; Transglutaminase 2