Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Endocr Relat Cancer. 2021 May 11;28(6):R141-R155. doi: 10.1530/ERC-20-0517.
Prostate cancer (CaP) remains the second leading cause of cancer deaths in Western men. These deaths occur because metastatic CaP acquires resistance to available treatments. The novel and functionally diverse treatment options that have been introduced in the clinic over the past decade each eventually induce resistance for which the molecular basis is diverse. Both initiation and progression of CaP have been associated with enhanced cell proliferation and cell cycle dysregulation. A better understanding of the specific pro-proliferative molecular shifts that control cell division and proliferation during CaP progression may ultimately overcome treatment resistance. Here, we examine literature for support of this possibility. We start by reviewing recently renewed insights in prostate cell types and their proliferative and oncogenic potential. We then provide an overview of the basic knowledge on the molecular machinery in charge of cell cycle progression and its regulation by well-recognized drivers of CaP progression such as androgen receptor and retinoblastoma protein. In this respect, we pay particular attention to interactions and reciprocal interplay between cell cycle regulators and androgen receptor. Somatic alterations that impact the cell cycle-associated and -regulated genes encoding p53, PTEN and MYC during progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP are discussed. We considered also non-genomic events that impact cell cycle determinants, including transcriptional, epigenetic and micro-environmental switches that occur during CaP progression. Finally, we evaluate the therapeutic potential of cell cycle regulators and address challenges and limitations in the approaches modulating their action for CaP treatment.
前列腺癌（CaP）仍然是西方男性癌症死亡的第二大主要原因。这些死亡是由于转移性 CaP 对现有治疗产生了耐药性。在过去十年中引入临床的新型、功能多样的治疗选择最终都诱导了耐药性，其分子基础各不相同。CaP 的起始和进展都与细胞增殖和细胞周期失调的增强有关。更好地了解控制 CaP 进展过程中细胞分裂和增殖的特定促增殖分子变化，可能最终克服治疗耐药性。在这里，我们研究文献以支持这种可能性。我们首先回顾了最近关于前列腺细胞类型及其增殖和致癌潜力的新见解。然后，我们概述了负责细胞周期进展的分子机制的基本知识，以及 CaP 进展的公认驱动因素，如雄激素受体和视网膜母细胞瘤蛋白，对细胞周期的调控。在这方面，我们特别关注细胞周期调节剂和雄激素受体之间的相互作用和相互作用。我们讨论了在从治疗初治、去势复发到某些情况下神经内分泌 CaP 的进展过程中，影响编码 p53、PTEN 和 MYC 的与细胞周期相关和受其调控的基因的体细胞改变。我们还考虑了影响细胞周期决定因素的非基因组事件，包括在 CaP 进展过程中发生的转录、表观遗传和微环境变化。最后，我们评估了细胞周期调节剂的治疗潜力，并探讨了调节其作用以治疗 CaP 的方法所面临的挑战和局限性。
