Budreika Audris, Phoenix John T, Kostlan Raymond J, Deegan Carleen D, Ferrari Marina G, Young Kristen S, Fanning Sean W, Kregel Steven
Department of Cancer Biology, Cardinal Bernardin Cancer Center, Stritch School of Medicine Health Sciences Division, Loyola University Chicago, 2160 South First Avenue Building 112, Room 205, Maywood, IL 60153, USA.
Integrated Program in Biomedical Science, Biochemistry, Molecular and Cancer Biology, Loyola University Chicago, Maywood, IL 60153, USA.
Cancers (Basel). 2025 Jan 18;17(2):306. doi: 10.3390/cancers17020306.
BACKGROUND/OBJECTIVES: Prostate cancer (PCa) is the second leading cause of cancer-related death in men. The increase in incidence rates of more advanced and aggressive forms of the disease year-to-year fuels urgency to find new therapeutic interventions and bolster already established ones. PCa is a uniquely targetable disease in that it is fueled by male hormones (androgens) that drive tumorigenesis via the androgen receptor or AR. Current standard-of-care therapies directly target AR and its aberrant signaling axis but resistance to these therapies commonly arises, and the mechanisms behind the onset of therapy-resistance are still elusive. Research has shown that even with resistant disease, AR remains the main driver of growth and survival of PCa, and AR target genes and cofactors may help mediate resistance to therapy. Here, we focused on a homeobox transcription factor that exhibits a close relationship with AR-NKX3.1. Though NKX3.1 is traditionally thought of as a tumor suppressor, it has been previously reported to promote cancer cell survival by cooperating with AR. The role of NKX3.1 as a tumor suppressor perhaps in early-stage disease also contradicts its profile as a diagnostic biomarker for advanced prostate cancer.
We investigated the physical interaction between NKX3.1 and AR, a modulated NKX3.1 expression in prostate cancer cells via overexpression and knockdown and assayed subsequent viability and downstream target gene expression.
We find that the expression of NKX3.1 is maintained in advanced PCa, and it is often elevated because of aberrant AR activity. Transient knockdown experiments across various PCa cell line models reveal NKX3.1 expression is necessary for survival. Similarly, stable overexpression of NKX3.1 in PCa cell lines reveals an androgen insensitive phenotype, suggesting NKX3.1 is sufficient to promote growth in the absence of an AR ligand.
Our work provides new insight into NKX3.1's oncogenic influence on PCa and the molecular interplay of these transcription factors in models of late-stage prostate cancer.
背景/目的：前列腺癌（PCa）是男性癌症相关死亡的第二大主要原因。该疾病更晚期和侵袭性形式的发病率逐年上升，这促使人们迫切需要寻找新的治疗干预措施并加强现有的治疗方法。PCa是一种具有独特靶向性的疾病，因为它由雄性激素（雄激素）驱动，这些雄激素通过雄激素受体（AR）促进肿瘤发生。当前的标准治疗方法直接靶向AR及其异常信号轴，但对这些治疗的耐药性通常会出现，并且治疗耐药性产生的机制仍然难以捉摸。研究表明，即使患有耐药性疾病，AR仍然是PCa生长和存活的主要驱动因素，AR靶基因和辅助因子可能有助于介导对治疗的耐药性。在这里，我们重点研究了一种与AR-NKX3.1关系密切的同源框转录因子。尽管传统上认为NKX3.1是一种肿瘤抑制因子，但此前有报道称它通过与AR合作促进癌细胞存活。NKX3.1作为早期疾病中肿瘤抑制因子的作用也与其作为晚期前列腺癌诊断生物标志物的特征相矛盾。
我们研究了NKX3.1与AR之间的物理相互作用，通过过表达和敲低在前列腺癌细胞中调节NKX3.1的表达，并检测随后的细胞活力和下游靶基因表达。
我们发现NKX3.1的表达在晚期PCa中得以维持，并且由于AR活性异常，其表达常常升高。在各种PCa细胞系模型中进行的瞬时敲低实验表明，NKX3.1的表达是细胞存活所必需的。同样，在PCa细胞系中稳定过表达NKX3.1会显示出雄激素不敏感表型，这表明NKX3.1足以在没有AR配体的情况下促进生长。
我们的工作为NKX3.1对PCa的致癌影响以及这些转录因子在晚期前列腺癌模型中的分子相互作用提供了新的见解。
