PO.ET03.02 · 实验与分子治疗
谱系特异性生存型与增殖型enzalutamide耐药状态作为前列腺癌差异的潜在驱动因素
Lineage-specific survival vs proliferative enzalutamide resistance states as potential drivers of prostate cancer disparities
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
非裔美国（AA）男性承受着不成比例的前列腺癌负担，其发病率和死亡率均高于非西班牙裔白人美国（NHWA）男性。治疗耐药是前列腺癌相关死亡的主要驱动因素，而AA患者对现有治疗的应答往往较差。Enzalutamide是一种第二代雄激素受体信号抑制剂，广泛用于治疗晚期转移性前列腺癌。为研究enzalutamide耐药的谱系特异性机制，我们通过逐步增加enzalutamide暴露，构建了源自AA的MDAPCa2b和源自NHWA的LNCaP细胞系的耐药衍生细胞。随后我们进行了基于RNA测序的转录组学分析，并整合了基因集富集分析（GSEA）、过度表达分析（ORA）和KEGG通路分析。将Enz-R细胞与其各自的亲本细胞系进行比较，鉴定出多个耐药相关差异表达基因（DEG），揭示了谱系特异性的转录程序。值得注意的是，MDAPCa2b Enz-R细胞表现出侵袭性、难治性前列腺癌特有的强大生存程序。尽管这些细胞保留了可测量的增殖能力，但它们采取了一种类似持留细胞的、代谢最小化的状态，其特征是氧化磷酸化、糖酵解、磷酸戊糖途径、氨基酸和tRNA生物合成、核糖体生物发生以及蛋白酶体活性的协同下调。KEGG分析显示凋亡受到抑制，包括TRAIL/TNFRSF10信号传导的丧失以及CASP10、BID和TP53的降低。这种代谢静止与抗凋亡保护的组合反映了一种生存优化的表型，与谱系可塑性、治疗耐受以及AA前列腺癌中常见的侵袭性疾病进程相关。相比之下，Enz-R LNCaP细胞表现出一种截然不同的增殖型耐药状态，其特征是细胞周期进程、DNA复制、同源重组、错配修复和碱基切除修复、p53信号传导以及嘧啶代谢的协同上调。免疫应答和黏附通路普遍下调，与免疫逃逸、AR非依赖性表型相一致。这种增殖性重塑代表了一条由AR旁路和强化的基因组维持通路驱动的经典逃逸途径。总之，这些发现凸显了两种截然不同的耐药策略：MDAPCa2b细胞中生存优化、代谢受抑、抗凋亡的程序，以及LNCaP细胞中增殖性、DNA修复增强的程序。这些生物学上分歧的进程可能促成了观察到的临床差异，并强调了对个体化、谱系导向治疗策略的需求。
查看英文原文 English abstract
African American (AA) men bear a disproportionate burden of prostate cancer, exhibiting higher incidence and mortality rates than their non-Hispanic White American (NHWA) counterparts. Therapeutic resistance is a major driver of prostate cancer-related mortality, and AA patients often show poorer responses to available treatments. Enzalutamide is a second-generation androgen receptor signaling inhibitor widely used to treat advanced metastatic prostate cancer. To investigate lineage-specific mechanisms of enzalutamide resistance, we generated resistant derivatives of the AA-origin MDAPCa2b and the NHWA-origin LNCaP cell lines by gradually increasing enzalutamide exposure. We then performed RNA sequencing-based transcriptomic profiling and integrated gene set enrichment analysis (GSEA), overrepresentation analysis (ORA), and KEGG pathway analysis. Comparison of Enz-R cells with their respective parental lines identified several resistance-associated differentially expressed genes (DEGs), revealing lineage-specific transcriptional programs. Notably, MDAPCa2b Enz-R cells exhibited a robust survival program characteristic of aggressive, therapy-refractory prostate cancer. Although these cells retained a measurable proliferative capacity, they adopted a persister-like, metabolically minimized state, marked by the coordinated downregulation of oxidative phosphorylation, glycolysis, pentose phosphate pathway, amino acid and tRNA biosynthesis, ribosome biogenesis, and proteasomal activity. KEGG analysis revealed apoptosis suppression, including loss of TRAIL/TNFRSF10 signaling and reduced CASP10, BID, and TP53. This combination of metabolic quiescence and anti-apoptotic protection reflects a survival-optimized phenotype associated with lineage plasticity, therapeutic tolerance, and the aggressive disease trajectories commonly observed in AA prostate cancer. In contrast, Enz-R LNCaP cells exhibited a distinct proliferative resistance state, marked by coordinated upregulation of cell-cycle progression, DNA replication, homologous recombination, mismatch and base-excision repair, p53 signaling, and pyrimidine metabolism. Immune response and adhesion pathways were broadly downregulated, consistent with an immune-evasive, AR-independent phenotype. This proliferative remodeling represents a canonical escape route driven by AR bypass and strengthened genome maintenance pathways. Together, these findings highlight two distinct resistance strategies: a survival-optimized, metabolically repressed, apoptosis resistant program in MDAPCa2b cells and a proliferative, DNA-repair enhanced program in LNCaP cells. These biologically divergent trajectories may contribute to observed clinical disparities and underscore the need for tailored, lineage-informed therapeutic strategies.
利益披露 Disclosure
R. Van, None..
M. V. Han, None..
D. P. Sharma, None..
A. Singh, None..
R. Mitra, None.