膜运输和细胞器接触位点在调节细胞代谢和生存中起着重要作用，而这些过程在癌症中经常发生紊乱。在发达国家，前列腺癌是男性癌症相关死亡的第二大原因。虽然早期疾病可以通过手术或放射治疗治愈，但在中晚期疾病中有一个未满足的需求，即确定预后生物标志物，治疗反应标志物和新的治疗靶点。本研究探讨了正常、低和中间组织学分级组的肿瘤组织中细胞器和膜接触位点的形态学。在一系列格里森分级的前列腺组织样本中，分泌前列腺上皮细胞中的细胞器形态学，包括高尔基体、内质网和溶酶体，相似。线粒体形态学没有明显改变，但与内质网的膜接触数量随着疾病进展明显增加。相比于正常组织，中间格里森分级组中紧密的线粒体-内质网膜接触位点增加了三倍。为了调查这些变化是否与组织中雄激素信号增加有关，我们调查了一种用于治疗晚期前列腺癌的抗雄激素药物（恩替卡韦）是否能逆转这种表型。用中间格里森分级得出的患者来源片段组织在体外培养，在有无恩替卡韦的条件下，对每对匹配的组织进行了内质网-线粒体接触位点数量的定量。恩替卡韦治疗组织显示出线粒体-内质网接触位点数量和长度的显著减少，表明这些膜接触位点可能是一种新的雄激素依赖性调节机制。本研究首次提供证据，表明前列腺上皮细胞在前列腺癌进展过程中经历了线粒体和内质网之间膜接触位点的调整。这些调整是雄激素依赖性的，并提供了一种支持多功能膜的建立和扩展的新的激素调节机制的证据。未来的研究将确定这些变化是否对维持前列腺癌细胞增殖信号和代谢变化的能力至关重要。版权 © 2023 Butler and Evergren.

Membrane trafficking and organelle contact sites are important for regulating cell metabolism and survival; processes often deregulated in cancer. Prostate cancer is the second leading cause of cancer-related death in men in the developed world. While early-stage disease is curable by surgery or radiotherapy there is an unmet need to identify prognostic biomarkers, markers to treatment response and new therapeutic targets in intermediate-late stage disease. This study explored the morphology of organelles and membrane contact sites in tumor tissue from normal, low and intermediate histological grade groups. The morphology of organelles in secretory prostate epithelial cells; including Golgi apparatus, ER, lysosomes; was similar in prostate tissue samples across a range of Gleason scores. Mitochondrial morphology was not dramatically altered, but the number of membrane contacts with the ER notably increased with disease progression. A three-fold increase of tight mitochondria-ER membrane contact sites was observed in the intermediate Gleason score group compared to normal tissue. To investigate whether these changes were concurrent with an increased androgen signaling in the tissue, we investigated whether an anti-androgen used in the clinic to treat advanced prostate cancer (enzalutamide) could reverse the phenotype. Patient-derived explant tissues with an intermediate Gleason score were cultured ex vivo in the presence or absence of enzalutamide and the number of ER-mitochondria contacts were quantified for each matched pair of tissues. Enzalutamide treated tissue showed a significant reduction in the number and length of mitochondria-ER contact sites, suggesting a novel androgen-dependent regulation of these membrane contact sites. This study provides evidence for the first time that prostate epithelial cells undergo adaptations in membrane contact sites between mitochondria and the ER during prostate cancer progression. These adaptations are androgen-dependent and provide evidence for a novel hormone-regulated mechanism that support establishment and extension of MAMs. Future studies will determine whether these changes are required to maintain pro-proliferative signaling and metabolic changes that support prostate cancer cell viability.Copyright © 2023 Butler and Evergren.