Transgenic Expression Of Mitochondrial Chaperone Trap1 Accelerates Prostate Cancer Development. Mus musculus

Protein homeostasis, or proteostasis is critical for organelle function, including mitochondria, but its role in cancer is controversial. Here, we show that transgenic mice expressing the mitochondrial chaperone, TRAP1 in the prostate develop prostatic hyperplasia and cellular atypia. When examined on a Pten+/- background, a common alteration in prostate cancer patients, TRAP1 transgenic mice showed accelerated incidence of invasive prostatic adenocarcinoma, characterized by increased cell proliferation and reduced apoptosis, in situ. Conversely, homozygous deletion of TRAP1 delays prostatic tumorigenesis in Pten+/- mice, without affecting hyperplasia or prostatic intraepithelial neoplasia (PIN). Global RNA sequencing and reverse phase protein array profiling of Pten+/--TRAP1 transgenic tumors reveals modulation of oncogenic networks of cell proliferation, apoptosis, cell motility, DNA damage and metabolism. Mechanistically, reconstitution of Pten+/- prostatic epithelial cells with TRAP1 results in increased cell proliferation, reduced apoptosis, heightened cell invasion, and no changes in mitochondrial bioenergetics. Therefore, TRAP1 promotes invasive prostate cancer, and provides an “actionable” therapeutic target in patients with advanced disease. Overall design: RNA-seq for Pten +/- mice with and without transgenic Trap1

蛋白质稳态（Protein homeostasis，又称proteostasis）对包括线粒体在内的细胞器功能至关重要，但其在癌症中的作用仍存在争议。本研究证实，在前列腺中过表达线粒体分子伴侣TRAP1的转基因小鼠可出现前列腺增生与细胞异型性。当在Pten+/-——这一前列腺癌患者中常见的分子改变——背景下开展研究时，TRAP1转基因小鼠的侵袭性前列腺腺癌发生率显著升高，其特征为原位细胞增殖增强、凋亡受抑。反之，在Pten+/-小鼠中纯合敲除TRAP1可延缓前列腺肿瘤发生，且不影响前列腺增生与前列腺上皮内瘤变（prostatic intraepithelial neoplasia, PIN）。对Pten+/-TRAP1转基因肿瘤进行全转录组RNA测序与反相蛋白芯片（reverse phase protein array）分析后发现，TRAP1可调控细胞增殖、凋亡、细胞运动、DNA损伤与代谢等致癌信号网络。机制层面，在Pten+/-前列腺上皮细胞中重新表达TRAP1可促进细胞增殖、抑制凋亡、增强细胞侵袭能力，且未改变线粒体生物能学特性。综上，TRAP1可促进侵袭性前列腺癌的发生发展，可为晚期前列腺癌患者提供可精准靶向的治疗靶点。实验整体设计：对携带与不携带Trap1转基因的Pten+/-小鼠进行RNA测序。