Abstract:
The androgen receptor (AR) is a key driver of prostate cancer (PCa) and, as such, current mainstay treatments target this molecule. However, resistance commonly arises to these therapies and, therefore, additional targets must be evaluated to improve patient outcomes. Consequently, alternative approaches for indirectly targeting the AR are sought. AR crosstalk with other signalling pathways, including several protein kinase signalling cascades, has been identified as a potential route to combat therapy resistance. The casein kinase 1 (CK1) family of protein kinases phosphorylate a multitude of substrates, allowing them to regulate a diverse range of pathways from the cell cycle to DNA damage repair. As well as its role in several signalling pathways that are de-regulated in PCa, mutational data suggest its potential to promote prostate carcinogenesis. CK1α is one isoform predicted to regulate AR activity via phosphorylation and has been implicated in the progression of several other cancer types. In this review, we explore how the normal biological function of CK1 is de-regulated in cancer, the impact on signalling pathways and how this contributes towards prostate tumourigenesis, with a particular focus on the CK1α isoform as a novel therapeutic target for PCa.
摘要:
雄激素受体(AR)是前列腺癌(PCa)的关键驱动因素,因此,当前的主流治疗针对该分子。然而,这些疗法通常会产生耐药性,因此,必须评估其他目标以改善患者预后.因此,寻求间接靶向AR的替代方法。AR与其他信号通路的串扰,包括几个蛋白激酶信号级联,已被确定为对抗治疗耐药性的潜在途径。蛋白激酶的酪蛋白激酶1(CK1)家族磷酸化多种底物,允许它们调节从细胞周期到DNA损伤修复的各种途径。以及它在PCa中下调的几种信号通路中的作用,突变数据表明它有可能促进前列腺癌的发生。CK1α是一种预测通过磷酸化调节AR活性的同种型,并与几种其他癌症类型的进展有关。在这次审查中,我们探讨CK1的正常生物学功能是如何在癌症中下调的,对信号通路的影响以及这如何促进前列腺肿瘤发生,特别关注CK1α同种型作为PCa的新治疗靶标。