Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Br J Cancer. 2018 Feb 6;118(3):416-420. doi: 10.1038/bjc.2017.404. Epub 2017 Nov 14.
We previously demonstrated that a seminal plasma protein, semenogelin I (SgI), functioned as an androgen receptor (AR) coactivator. Meanwhile, several short sequence motifs in AR coregulators, such as LxxLL (L=leucine), have been shown to mediate specific interactions with AR.
We investigated the role of the LxxLL motif within SgI in the interactions with AR and cell growth in prostate cancer lines in vitro.
A full-length SgI with mutations in the motif (i.e., LxxAA; A=alanine) failed to significantly increase cell proliferation/migration as well as androgen-mediated AR transcription. Co-immunoprecipitation showed no physical interactions between AR and the mutant SgI. In addition, transfection of an 18-amino acid peptide of SgI containing LxxLL, but not LxxAA, resulted in considerable reduction in cell growth and prostate-specific antigen expression in LNCaP and C4-2 lines.
The LxxLL motif of SgI could be a novel therapeutic target for both androgen-sensitive and castration-resistant prostate cancers.
我们之前证明了精浆蛋白精液蛋白 I（SgI）可作为雄激素受体（AR）共激活剂发挥作用。同时，AR 共调节剂中的几个短序列基序，如 LxxLL（L=亮氨酸），已被证明可介导与 AR 的特异性相互作用。
我们研究了 SgI 中 LxxLL 基序在体外前列腺癌细胞系中与 AR 的相互作用和细胞生长中的作用。
该 motif（即 LxxAA；A=丙氨酸）发生突变的全长 SgI 不能显著增加细胞增殖/迁移以及雄激素介导的 AR 转录。共免疫沉淀显示 AR 和突变型 SgI 之间没有物理相互作用。此外，转染含有 LxxLL 但不含 LxxAA 的 SgI 的 18 个氨基酸肽，可导致 LNCaP 和 C4-2 细胞系中的细胞生长和前列腺特异性抗原表达显著减少。
SgI 的 LxxLL 基序可能成为治疗雄激素敏感和去势抵抗性前列腺癌的新靶点。
