Department of Genitourinary Medical Oncology, Unit 18-3, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Mol Oncol. 2013 Jun;7(3):484-96. doi: 10.1016/j.molonc.2012.12.005. Epub 2012 Dec 31.
In this study we report that expression of glioma pathogenesis-related protein 1 (GLIPR1) regulated numerous apoptotic, cell cycle, and spindle/centrosome assembly-related genes, including AURKA and TPX2, and induced apoptosis and/or mitotic catastrophe (MC) in prostate cancer (PCa) cells, including p53-mutated/deleted, androgen-insensitive metastatic PCa cells. Mechanistically, GLIPR1 interacts with heat shock cognate protein 70 (Hsc70); this interaction is associated with SP1 and c-Myb destabilization and suppression of SP1- and c-Myb-mediated AURKA and TPX2 transcription. Inhibition of AURKA and TPX2 using siRNA mimicked enforced GLIPR1 expression in the induction of apoptosis and MC. Recombinant GLIPR1-ΔTM protein inhibited AURKA and TPX2 expression, induced apoptosis and MC, and suppressed orthotopic xenograft tumor growth. Our results define a novel GLIPR1-regulated signaling pathway that controls apoptosis and/or mitotic catastrophe in PCa cells and establishes the potential of this pathway for targeted therapies.
在这项研究中，我们报告Glioma 发病相关蛋白 1（GLIPR1）的表达调控了许多与凋亡、细胞周期和纺锤体/中心体组装相关的基因，包括 AURKA 和 TPX2，并诱导包括 p53 突变/缺失、雄激素不敏感转移性前列腺癌（PCa）细胞在内的 PCa 细胞发生凋亡和/或有丝分裂灾难（MC）。在机制上，GLIPR1 与热休克同源蛋白 70（Hsc70）相互作用；这种相互作用与 SP1 和 c-Myb 的不稳定以及 SP1 和 c-Myb 介导的 AURKA 和 TPX2 转录的抑制有关。使用 siRNA 抑制 AURKA 和 TPX2 可模拟强制表达 GLIPR1 诱导的凋亡和 MC。重组 GLIPR1-ΔTM 蛋白抑制 AURKA 和 TPX2 的表达，诱导凋亡和 MC，并抑制原位异种移植肿瘤的生长。我们的结果定义了一个新的 GLIPR1 调控的信号通路，该通路控制 PCa 细胞中的凋亡和/或有丝分裂灾难，并为靶向治疗建立了该通路的潜力。
