Zhang Liyong, Zhao Zhenlong, Xu Shuping, Tandon Manuj, LaValle Courtney R, Deng Fan, Wang Q Jane
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Oncotarget. 2017 Feb 21;8(8):12800-12811. doi: 10.18632/oncotarget.14536.
In prostate cancer, androgen/androgen receptor (AR) and their downstream targets play key roles in all stages of disease progression. The protein kinase D (PKD) family, particularly PKD1, has been implicated in prostate cancer biology. Here, we examined the cross-regulation of PKD1 by androgen signaling in prostate cancer cells. Our data showed that the transcription of PKD1 was repressed by androgen in androgen-sensitive prostate cancer cells. Steroid depletion caused up regulation of PKD1 transcript and protein, an effect that was reversed by the AR agonist R1881 in a time- and concentration-dependent manner, thus identifying PKD1 as a novel androgen-repressed gene. Kinetic analysis indicated that the repression of PKD1 by androgen required the induction of a repressor protein. Furthermore, inhibition or knockdown of AR reversed AR agonist-induced PKD1 repression, indicating that AR was required for the suppression of PKD1 expression by androgen. Downstream of AR, we identified fibroblast growth factor receptor substrate 2 (FRS2) and its downstream MEK/ERK pathway as mediators of androgen-induced PKD1 repression. In summary, PKD1 was identified as a novel androgen-suppressed gene and could be downregulated by androgen through a novel AR/FRS2/MEK/ERK pathway. The upregulation of prosurvival PKD1 by anti-androgens may contribute to therapeutic resistance in prostate cancer treatment.
在前列腺癌中，雄激素/雄激素受体（AR）及其下游靶点在疾病进展的各个阶段都起着关键作用。蛋白激酶D（PKD）家族，尤其是PKD1，已被证明与前列腺癌生物学有关。在此，我们研究了前列腺癌细胞中雄激素信号对PKD1的交叉调控。我们的数据表明，在雄激素敏感的前列腺癌细胞中，雄激素可抑制PKD1的转录。去除类固醇会导致PKD1转录本和蛋白的上调，而AR激动剂R1881可呈时间和浓度依赖性地逆转这种效应，从而确定PKD1是一种新的雄激素抑制基因。动力学分析表明，雄激素对PKD1的抑制需要诱导一种阻遏蛋白。此外，抑制或敲低AR可逆转AR激动剂诱导的PKD1抑制，这表明AR是雄激素抑制PKD1表达所必需的。在AR的下游，我们确定成纤维细胞生长因子受体底物2（FRS2）及其下游的MEK/ERK途径是雄激素诱导的PKD1抑制的介质。总之，PKD1被确定为一种新的雄激素抑制基因，并且雄激素可通过一种新的AR/FRS2/MEK/ERK途径下调PKD1。抗雄激素药物上调促生存的PKD1可能会导致前列腺癌治疗中的耐药性。
