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SLX4IP-mediated telomere maintenance is essential for androgen receptor-independent castration-resistant prostate cancer
bioRxiv - Cancer Biology Pub Date : 2020-06-04 , DOI: 10.1101/2020.03.31.018846
Tawna L. Mangosh , Wisam N. Awadallah , Magdalena M. Grabowska , Derek J. Taylor

In advanced prostate cancer, resistance to androgen deprivation therapy is achieved through numerous mechanisms, including loss of the androgen receptor (AR) allowing for AR-independent growth. Therapeutic options are limited for AR-independent castration-resistant prostate cancer, and defining mechanisms critical for its survival is of utmost importance for targeting this lethal disease. Our studies have focused on defining the telomere maintenance mechanism (TMM) required for castration-resistant prostate cancer (CRPC) cell survival. TMMs are responsible for telomere elongation to instill replicative immortality and prevent senescence, with the two TMM pathways available being telomerase and alternative lengthening of telomeres (ALT). Here, we show that AR-independent CRPC exhibits ALT hallmarks and limited telomerase expression and activity, whereas AR-dependent models use telomerase for telomere maintenance. AR-independent CRPC exhibited elevated levels of SLX4IP, a protein implicated in TMM switching. SLX4IP overexpression in AR-dependent CRPC C4-2B cells promoted ALT hallmarks in vitro. SLX4IP knockdown in AR-independent CRPC cells (DU145 and PC-3) led to the loss of ALT hallmarks, dramatic telomere shortening, induction of senescence, and reduced tumor volume. Using an in vitro model of CRPC progression, induction of neuroendocrine differentiation in AR-dependent CRPC cells promoted ALT hallmarks in an SLX4IP-dependent manner. Lack of sufficient SLX4IP expression prevented ALT hallmarks rendering a TMM deficient environment, thus inducing senescence. This study demonstrates a unique reliance of AR-independent CRPC on SLX4IP-mediated ALT. Furthermore, ALT hallmark inhibition via SLX4IP induces senescence, thereby abolishing the replicative immortality of AR-independent CRPC.

中文翻译:

SLX4IP介导的端粒维持对于雄激素受体依赖性去势抵抗性前列腺癌至关重要

在晚期前列腺癌中,通过多种机制实现了对雄激素剥夺治疗的抵抗力,包括雄激素受体(AR)的丧失使AR非依赖性生长成为可能。对于不依赖AR的去势抵抗性前列腺癌,治疗选择受到限制,并且确定对其生存至关重要的机制对于靶向这种致命性疾病至关重要。我们的研究集中在定义去势抵抗性前列腺癌(CRPC)细胞存活所需的端粒维持机制(TMM)。TMM负责端粒的延长以灌输复制性永生并防止衰老,可用的两种TMM途径是端粒酶和端粒的替代性延长(ALT)。在这里,我们显示了独立于AR的CRPC表现出ALT标志,并且端粒酶的表达和活性受到限制,而依赖AR的模型使用端粒酶进行端粒维护。不依赖AR的CRPC表现出高水平的SLX4IP,这是一种与TMM转换有关的蛋白。依赖AR的CRPC C4-2B细胞中的SLX4IP过表达在体外促进了ALT标志。不依赖AR的CRPC细胞(DU145和PC-3)中的SLX4IP敲低导致ALT标志丧失,端粒急剧缩短,衰老诱导和肿瘤体积减小。使用CRPC进展的体外模型,在AR依赖性CRPC细胞中诱导神经内分泌分化以SLX4IP依赖性方式促进了ALT标志。缺乏足够的SLX4IP表达会阻止ALT标志形成TMM缺陷环境,从而引起衰老。这项研究证明了独立于AR的CRPC对SLX4IP介导的ALT的独特依赖。此外,
更新日期:2020-06-04
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