The androgen receptor/filamin A complex as a target in prostate cancer microenvironment.
The androgen receptor/filamin A complex as a target in prostate cancer microenvironment.
复制标题
DOI：
10.1038/s41419-021-03402-7
复制
发表时间：
2021-01-26
影响因子：
9
通讯作者：
Castoria G
中科院分区：
文献类型：
--
作者：
Di Donato M;Zamagni A;Galasso G;Di Zazzo E;Giovannelli P;Barone MV;Zanoni M;Gunelli R;Costantini M;Auricchio F;Migliaccio A;Tesei A;Castoria G
前列腺癌是男性癌症相关死亡的主要原因，患者经常出现耐药性和转移性疾病。大多数研究集中在与雄激素受体突变或前列腺癌细胞获得性过度激活信号通路相关的激素耐药机制上。肿瘤微环境在前列腺癌的发展中起着至关重要的作用。然而，癌症相关成纤维细胞中雄激素/雄激素受体信号传导的机制及其对前列腺癌进展的影响仍不明确。我们现在报道前列腺癌相关成纤维细胞表达一种转录功能不全的雄激素受体。在雄激素刺激下，受体与成纤维细胞核外室中的支架蛋白丝蛋白A共定位，从而介导成纤维细胞的迁移和侵袭。在2D和3D培养中，癌症相关成纤维细胞向上皮性前列腺癌细胞移动，从而诱导前列腺癌类器官大小的增加。雄激素通过雄激素受体/丝蛋白A复合物在癌症相关成纤维细胞中的组装来增强这两种作用。雄激素受体衍生的钉状肽，破坏雄激素受体/丝蛋白A复合物组装，消除雄激素依赖性迁移和癌症相关成纤维细胞的侵袭性。值得注意的是，在2D模型中，该肽削弱了雄激素诱导的cas侵袭性，并在雄激素处理的3D共培养中减少了肿瘤的总体面积。雄激素受体与β1整合素和膜型基质金属蛋白酶1相关，激活蛋白酶级联触发细胞外基质重塑。这种肽也会损害这个级联的雄激素激活。这项研究为前列腺癌相关成纤维细胞中雄激素受体/丝蛋白a复合物提供了一个潜在的新标志物，并为雄激素/雄激素受体轴激活的细胞内通路提供了一种新的治疗方法。这样的策略，单独或与传统疗法相结合，可以更有效地治疗前列腺癌。
Prostate cancer represents the major cause of cancer-related death in men and patients frequently develop drug-resistance and metastatic disease. Most studies focus on hormone-resistance mechanisms related to androgen receptor mutations or to the acquired property of prostate cancer cells to over-activate signaling pathways. Tumor microenvironment plays a critical role in prostate cancer progression. However, the mechanism involving androgen/androgen receptor signaling in cancer associated fibroblasts and consequences for prostate cancer progression still remains elusive. We now report that prostate cancer associated fibroblasts express a transcriptional-incompetent androgen receptor. Upon androgen challenging, the receptor co-localizes with the scaffold protein filamin A in the extra-nuclear compartment of fibroblasts, thus mediating their migration and invasiveness. Cancer-associated fibroblasts move towards epithelial prostate cancer cells in 2D and 3D cultures, thereby inducing an increase of the prostate cancer organoid size. Androgen enhances both these effects through androgen receptor/filamin A complex assembly in cancer-associated fibroblasts. An androgen receptor-derived stapled peptide, which disrupts the androgen receptor/filamin A complex assembly, abolishes the androgen-dependent migration and invasiveness of cancer associated fibroblasts. Notably, the peptide impairs the androgen-induced invasiveness of CAFs in 2D models and reduces the overall tumor area in androgen-treated 3D co-culture. The androgen receptor in association with β1 integrin and membrane type-matrix metalloproteinase 1 activates a protease cascade triggering extracellular matrix remodeling. The peptide also impairs the androgen activation of this cascade. This study offers a potential new marker, the androgen receptor/filamin A complex, and a new therapeutic approach targeting intracellular pathways activated by the androgen/androgen receptor axis in prostate cancer-associated fibroblasts. Such a strategy, alone or in combination with conventional therapies, may allow a more efficient treatment of prostate cancer.
登录
查看更多内容
雌激素及其受体在前列腺癌中：治疗意义。
影响因子：
4.7
作者：
Di Zazzo E;Galasso G;Giovannelli P;Di Donato M;Castoria G
通讯作者：
Castoria G
DOI：
10.1158/1078-0432.ccr-08-1402
发表时间：
2009-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bedolla RG;Wang Y;Asuncion A;Chamie K;Siddiqui S;Mudryj MM;Prihoda TJ;Siddiqui J;Chinnaiyan AM;Mehra R;de Vere White RW;Ghosh PM
通讯作者：
Ghosh PM
影响因子：
9
作者：
Castoria G;Giovannelli P;Di Donato M;Ciociola A;Hayashi R;Bernal F;Appella E;Auricchio F;Migliaccio A
通讯作者：
Migliaccio A
影响因子：
7.3
作者：
Ellem, Stuart J.;Taylor, Renea A.;Risbridger, Gail P.
通讯作者：
Risbridger, Gail P.
影响因子：
7
作者：
Di Donato M;Cernera G;Auricchio F;Migliaccio A;Castoria G
通讯作者：
Castoria G