Gao Lin, Han Bo, Dong Xuesen
Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Front Oncol. 2022 Jun 27;12:905398. doi: 10.3389/fonc.2022.905398. eCollection 2022.
While the androgen receptor (AR) signalling is the mainstay therapeutic target for metastatic prostate cancers, these tumours will inevitably develop therapy resistance to AR pathway inhibitors suggesting that prostate tumour cells possess the capability to develop mechanisms to bypass their dependency on androgens and/or AR to survive and progress. In many studies, protein kinases such as Src are reported to promote prostate tumour progression. Specifically, the pro-oncogene tyrosine Src kinase regulates prostate cancer cell proliferation, adhesion, invasion, and metastasis. Not only can Src be activated under androgen depletion, low androgen, and supraphysiological androgen conditions, but also through crosstalk with other oncogenic pathways. Reciprocal activations between Src and AR proteins had also been reported. These findings rationalize Src inhibitors to be used to treat castrate-resistant prostate tumours. Although several Src inhibitors had advanced to clinical trials, the failure to observe patient benefits from these studies suggests that further evaluation of the roles of Src in prostate tumours is required. Here, we summarize the interplay between Src and AR signalling during castrate-resistant prostate cancer progression to provide insights on possible approaches to treat prostate cancer patients.
虽然雄激素受体（AR）信号传导是转移性前列腺癌的主要治疗靶点，但这些肿瘤不可避免地会对AR通路抑制剂产生治疗抗性，这表明前列腺肿瘤细胞具有发展出绕过其对雄激素和/或AR的依赖性以存活和进展的机制的能力。在许多研究中，据报道诸如Src等蛋白激酶可促进前列腺肿瘤进展。具体而言，原癌基因酪氨酸Src激酶调节前列腺癌细胞的增殖、黏附、侵袭和转移。Src不仅可在雄激素耗竭、低雄激素和超生理雄激素条件下被激活，还可通过与其他致癌途径的串扰被激活。Src与AR蛋白之间的相互激活也有报道。这些发现使Src抑制剂用于治疗去势抵抗性前列腺肿瘤具有合理性。尽管几种Src抑制剂已进入临床试验，但这些研究未能观察到患者获益，这表明需要进一步评估Src在前列腺肿瘤中的作用。在此，我们总结了去势抵抗性前列腺癌进展过程中Src与AR信号传导之间的相互作用，以提供关于治疗前列腺癌患者可能方法的见解。
