Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio.
Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio.
Cancer Res. 2023 Dec 15;83(24):4142-4160. doi: 10.1158/0008-5472.CAN-23-0883.
Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression. Increased CIT expression correlated with prostate cancer growth induction and aggressive prostate cancer progression, and CIT was overexpressed in prostate cancer compared with benign prostate tissue. CIT overexpression was controlled by an E2F2-Skp2-p27 signaling axis and conferred resistance to androgen-targeted treatment strategies. The effects of CIT relied entirely on its kinase activity. Conversely, CIT silencing inhibited the growth of cell lines and xenografts representing different stages of prostate cancer progression and treatment resistance but did not affect benign epithelial prostate cells or nonprostatic normal cells, indicating a potential therapeutic window for CIT inhibition. CIT kinase activity was identified as druggable and was potently inhibited by the multikinase inhibitor OTS-167, which decreased the proliferation of treatment-resistant prostate cancer cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant prostate cancer. These findings provide insights into the regulation of aggressive prostate cancer cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of prostate cancer progression.
The poorly characterized protein kinase citron kinase is a therapeutic target in prostate cancer that drives tumor growth by regulating diverse substrates, which control several hallmarks of aggressive prostate cancer progression. See related commentary by Mishra et al., p. 4008.
在西方文化中，前列腺癌仍然是男性癌症死亡的第二大主要原因。更深入地了解前列腺癌细胞分裂以支持肿瘤生长的机制，可以帮助设计克服治疗耐药性和提高生存率的策略。在这里，我们发现有丝分裂 AGC 家族蛋白激酶 citron kinase（CIT）是前列腺癌生长的关键调节因子，介导前列腺癌细胞的间期进展。CIT 表达增加与前列腺癌生长诱导和侵袭性前列腺癌进展相关，并且 CIT 在前列腺癌中比良性前列腺组织过度表达。CIT 的过表达受 E2F2-Skp2-p27 信号轴的控制，并赋予对雄激素靶向治疗策略的耐药性。CIT 的作用完全依赖于其激酶活性。相反，CIT 沉默抑制了代表不同前列腺癌进展和治疗耐药阶段的细胞系和异种移植物的生长，但不影响良性上皮前列腺细胞或非前列腺正常细胞，表明 CIT 抑制具有潜在的治疗窗口。CIT 激酶活性被鉴定为可药物靶向，并且被多激酶抑制剂 OTS-167 强烈抑制，后者降低了治疗耐药的前列腺癌细胞和患者衍生的类器官的增殖。体内 CIT 底物的分离鉴定了涉及从增殖到替代剪接事件的多种细胞功能的蛋白质，这些蛋白质在治疗耐药的前列腺癌中富集。这些发现为 CIT 调节侵袭性前列腺癌细胞行为提供了深入的了解，并确定 CIT 为前列腺癌进展的功能多样且可药物靶向的驱动因素。
描述不清的蛋白激酶 citron kinase 是前列腺癌的治疗靶点，通过调节控制侵袭性前列腺癌进展的几个标志的多种底物来驱动肿瘤生长。见 Mishra 等人的相关评论，第 4008 页。
