向PCNA/AR相互作用抑制了AR介导的信号传递在抵抗割的前列腺癌细胞中
1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Oncotarget
|May 20, 2025
概括
针对增殖细胞核抗原 (PCNA) 和雄激素受体 (AR) 之间的相互作用,抑制前列腺癌的生长. 这种新的策略针对全长和变异性AR信号,为割抵抗性前列腺癌提供了一种新的治疗方法.
科学领域:
- 分子生物学分子生物学
- 在瘤学瘤学.
- 生物化学 生化学
背景情况:
- 增殖细胞核抗原 (PCNA) 通过PIP-box4与雄激素受体 (AR) 相互作用,调节AR活性.
- 雄激素受体 (AR) 信号传递是前列腺癌进展的关键驱动因素,特别是在抵抗割的前列腺癌 (CRPC) 中.
研究的目的:
- 进一步研究PCNA/AR相互作用,确定新的结合部位,并评估将这种相互作用作为CRPC治疗策略的向.
- 评估抑制PCNA/AR相互作用对CRPC模型中AR转录活性和下游基因表达的影响.
主要方法:
- 在ARDNA结合域中的第二个PIP-box (PIP-box592) 的识别.
- 用R9-AR-PIP (一种模仿PIP-box4的) 和PCNA-I1S (一种小分子PCNA抑制剂) 治疗AR阳性CRPC细胞.
- 评估AR占用在雄激素反应元素 (ARE),基因表达,转录活性和细胞毒性.
主要成果:
- 二增强了AR-FL与PCNA的结合,但没有增强AR-V7.
- R9-AR-PIP抑制PCNA/AR相互作用,PSA和p21基因中的AREs的AR占用,以及AR基因表达,导致CRPC细胞细胞毒性.
- R9-AR-PIP和PCNA-I1S都抑制了CCNA2基因ARE和环林A2表达的AR占用;环林A2在CRPC细胞中过度表达.
结论:
- 针对PCNA/AR相互作用有效地抑制了AR-FL和AR-V信号通路.
- 抑制PCNA/AR相互作用代表了对割抵抗性前列腺癌的有前途的新疗法策略.
- 在CRPC中过度表达环林A2表明其在疾病发展和作为治疗点的潜在作用.
相关概念视频
Inhibition of Cdk Activity
4.6K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.6K
Abnormal Proliferation
4.4K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.4K
Interactions Between Signaling Pathways
6.2K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.2K
Negative Regulator Molecules
35.1K
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
35.1K
Experimental RNAi
6.0K
RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
6.0K
mTOR Signaling and Cancer Progression
3.7K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.7K


