TLK1>Nek1轴促进核保留和YAP的激活,这对抗割的前列腺癌有影响
Damilola Olatunde1, Arrigo De Benedetti1
1Department of Biochemistry and Molecular Biology, The Feist Weiller Cancer Center, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA.
用J54准TLK1>NEK1轴通过去酸化YAP并防止其核保留来抑制前列腺癌的进展,为抵抗割的前列腺癌 (CRPC) 提供了一个新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症治疗方法 癌症治疗方法
背景情况:
- 前列腺癌 (PCa) 进展为抗割PCa (CRPC) 仍然是一个重大的临床挑战,需要对潜在机制有更深入的了解.
- 河马通路,特别是协同激活剂YAP,通过使受体 (AR) 信号连在低水平下也能够在CRPC中发挥关键作用.
- 最近的发现表明,TLK1>NEK1轴在Y407的Y407酸化过程中对YAP的转录后激活作用.
研究的目的:
- 在CRPC中阐明Y407处YAP酸化的功能意义.
- 在前列腺癌的临床前模型中研究使用J54 (TLK1抑制剂) 抑制TLK1>NEK1轴的治疗潜力.
主要方法:
- 研究了J54对YAP酸化,核保留和前列腺癌细胞降解的影响.
- 利用染色体免疫沉 (ChIP) 来评估YAP与向基因促进体的结合.
- 在LNCaP和VCaP异种移植模型中评估了ARSI和J54联合治疗的疗效.
主要成果:
- J54治疗逆转了Y407中的YAP酸化,减少了核YAP,并促进了细胞质YAP降解,抵消了因恩扎拉胺诱导的YAP积累.
- 化YAP (pYAP-Y407) 增强了与AR和TEAD1的关联,促进了YAP/AR基因的转录;J54破坏了这种相互作用.
- 与ARSI和J54的联合治疗诱导了LNCaP异种移植中的瘤回归,但VCaP瘤复发,尽管抑制了YAP,但表明了其他CRPC途径.
结论:
- 在Y407的YAP酸化对核保留和前列腺癌中AR/TEAD1基因的联合激活至关重要.
- 通过J54抑制TLK1>NEK1轴是一种有前途的策略,可以克服CRPC中的AR信号,特别是在对这种途径敏感的模型中.
- VCaP瘤的复发凸显了CRPC的复杂性和替代信号通路的潜力,这些信号通路可能需要超出针对YAP的组合疗法.
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