PO.EN01.01 · 内分泌肿瘤
白细胞介素-6在去势抵抗性前列腺癌细胞系模型中增加糖皮质激素的失活
Interleukin-6 increases glucocorticoid inactivation in a castration resistant prostate cancer cell line model
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
前列腺癌是美国男性癌症死亡的第二大原因。它依赖于雄激素受体（AR）信号传导，起初对阻断AR信号的疗法有反应。不幸的是，癌症复发并对这些疗法产生耐药的情况很常见，进而成为一种被称为去势抵抗性前列腺癌的形式。这种对AR阻断剂的耐药部分由糖皮质激素受体（GR）接管驱动增殖的AR靶基因调控所介导。正如我们团队和其他团队所展示的，AR阻断剂耐药肿瘤中的这种GR接管，部分是由于GR水平升高以及糖皮质激素失活酶11betaHSD2的丢失所致。研究肿瘤特异性活性糖皮质激素——皮质醇——水平的调控至关重要，因为它们决定了局部GR活性，因而与治疗耐药相关。在这项工作中，我们着手确定细胞因子如何调控11betaHSD2活性并影响前列腺癌中的糖皮质激素水平。
使用去势抵抗性前列腺癌细胞系模型（VCaP）并通过高效液相色谱追踪放射性标记的类固醇，我们表明白细胞介素-6（IL-6）增加11betaHSD2活性，促进糖皮质激素的代谢失活。我们表明白细胞介素-6增加HSD11B2（编码11betaHSD2）的转录本水平和11betaHSD2蛋白丰度，表明IL-6通过在转录水平上调HSD11B2驱动糖皮质激素失活的增加。使用瞬时siRNA敲低和选择性药理学抑制剂，我们表明阻断JAK1/2、gp130和STAT3可逆转这种糖皮质激素失活，因此它们是介导白细胞介素-6诱导的HSD11B2表达、蛋白水平和活性上调的必需信号元件。综合来看，我们发现白细胞介素-6和JAK/STAT信号传导是前列腺癌中糖皮质激素代谢的一个潜在新调节因子。进一步的工作将阐明其在疾病进展和治疗耐药背景下的生理和治疗意义。最终，本研究旨在加深对前列腺癌中糖皮质激素代谢调控及其在疾病恶化和治疗反应性中作用的理解。
查看英文原文 English abstract
Prostate cancer is the second leading cause of cancer deaths in men in the United States. It is dependent on androgen receptor (AR) signaling and initially is responsive to therapies blocking AR signaling. Unfortunately, it is common for the cancer to reoccur and become resistant to these therapies and become a form known as castration resistant prostate cancer. This resistance to AR blockers is in part mediated by the glucocorticoid receptor (GR) taking over the regulation of AR-target genes driving proliferation. As shown by our group and others, this GR take over in AR blocker resistant tumors is in part due to increases in GR levels and due to loss of the glucocorticoid-inactivating enzyme 11betaHSD2. Studying the regulation of the tumor-specific levels of the active glucocorticoid, cortisol, is essential as they determine local GR activity and are hence tied to therapeutic resistance. In this work, we set out to determine how cytokines regulate 11betaHSD2 activity and affect glucocorticoid levels in prostate cancer.
Using a cell line model of castration resistant prostate cancer (VCaP) and tracing of radiolabeled steroids by High Performance Liquid Chromatography, we show that interleukin-6 (IL-6) increases 11betaHSD2 activity, promoting metabolic inactivation of glucocorticoids. We show that interleukin-6 increases transcript levels of HSD11B2 (encoding 11betaHSD2) and 11betaHSD2 protein abundance indicating that IL-6 drives increased glucocorticoid inactivation by upregulating HSD11B2 at the transcriptional level. Using transient siRNA knockdowns and selective, pharmacological inhibitors, we show that blocking JAK1/2, gp130, and STAT3 results in reversal of this glucocorticoid inactivation and are therefore required signaling elements that mediate the interleukin-6 induced upregulation of HSD11B2 expression, protein level and activity in VCaP cells. Taken together, we have discovered interleukin-6 and JAK/STAT signaling as a potential new regulator of glucocorticoid metabolism in prostate cancer. Further work will elicit the physiological and therapeutic implications in the context of disease progression and therapy resistance. Ultimately, this research aims to deepen the understanding of glucocorticoid metabolism regulation in prostate cancer and its role in disease escalation and treatment responsiveness.
利益披露 Disclosure
O. M. Tonini, None..
L. Schiffer, None..
N. Sharifi, None.