Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
Eur J Cancer. 2014 Jun;50(9):1685-96. doi: 10.1016/j.ejca.2014.02.014. Epub 2014 Mar 20.
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.
许多研究都支持炎症在前列腺肿瘤生长中的作用。然而，炎症对去势抵抗性前列腺癌的发展的贡献在很大程度上仍然未知。基于异常表达促炎蛋白组织转谷氨酰胺酶（TG2）与多种癌症类型的耐药性和转移表型的发展相关的观察结果，我们确定了前列腺癌细胞中的 TG2 表达。在此，我们报告低表达雄激素受体（AR）的人前列腺癌细胞系具有高基础 TG2 表达水平。此外，TG2 的过表达负调节 AR mRNA 和蛋白表达，并减弱前列腺癌细胞对雄激素的敏感性。前列腺癌细胞中的 TG2 表达与侵袭增加和化疗耐药性有关。在机制上，TG2 激活核因子（NF）-κB 并诱导上皮-间充质转化。TG2/NF-κB 介导的 AR 表达下降是由于 NF-κB 与 TG2 的顺式相互作用与 AR 的 5'-非翻译区结合而涉及转录抑制。通过基因特异性小干扰 RNA 抑制 TG2 或 NF-κB（p65/RelA）可以部分阻断 AR 的负调控。这些结果表明，一种新的途径将雄激素依赖性与 TG2 调节的炎症信号联系起来，因此 TG2 可能成为预防和治疗去势抵抗性前列腺癌的新的治疗靶点。
