TP53 loss-of-function causes vulnerability to autophagy inhibition in aggressive prostate cancer
TP53 loss-of-function causes vulnerability to autophagy inhibition in aggressive prostate cancer
复制标题
TP53 功能丧失导致侵袭性前列腺癌易受自噬抑制的影响
DOI：
10.1111/iju.15021
复制
发表时间：
2022-08-17
影响因子：
2.6
通讯作者：
Chua，Chee Wai
中科院分区：
文献类型：
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作者：
Zhang，Yong;Song，Xian-Li;Chua，Chee Wai
目的TP53功能丧失常见于侵袭性前列腺癌。然而，针对这种肿瘤亚型的高效治疗仍然缺乏。本研究探讨了前列腺癌组织中TP53基因突变状态与自噬的关系，并评价了自噬抑制剂对TP53基因缺陷的前列腺癌组织的治疗效果。方法采用免疫组织化学方法，研究了前列腺癌组织中自噬相关蛋白LC3B、ULK1和BECLIN1的表达模式及其相互关系。随后，我们建立了TrP53缺失的基因工程小鼠模型，建立了小鼠的前列腺癌器官系，并评估了自噬抑制剂在克服肿瘤有机物模型中恩扎鲁胺耐药性方面的有效性。我们还利用含有TP53错义突变的LNCaP细胞株，研究了TP53re表达在调节自噬抑制剂反应中的影响。最后，我们试图确定潜在的自噬相关基因，这些基因对TP53缺失的肿瘤维持至关重要。结果在侵袭性前列腺癌和Trp53缺失的基因工程小鼠来源的肿瘤中，TP53功能丧失与自噬相关蛋白水平的增加有关。此外，产生的雄激素受体非依赖性肿瘤有机体非常容易受到自噬抑制。UponTP53re表达后，存活的LNCaP细胞不仅表现出抗性，而且对自噬抑制也表现出生长优势。最后，在具有TP53功能缺失突变的侵袭性肿瘤中，一种重要的过氧化体调节因子PEX14被差异地上调，从而暗示了在该肿瘤亚型中过氧化体周转的重要性。结论我们的结果支持自噬抑制剂在含有TP53功能缺失突变的前列腺癌中的潜在应用。
ObjectivesTP53loss‐of‐function is commonly found in aggressive prostate cancer. However, a highly‐efficient therapy for this tumor subtype is still lacking. In this study, we investigated the relationship betweenTP53mutation status and autophagy in prostate cancer and assessed the efficacy of autophagy inhibitors onTP53‐deficient tumors.MethodsWe first evaluated the expression patterns of p53 and autophagy‐related proteins, namely LC3B, ULK1 and BECLIN1, as well as their relationship in treatment‐naïve and castration‐resistant prostate cancer specimens through immunohistochemistry. Subsequently, we generated aTrp53‐deleted genetically‐engineered mouse model, established prostate tumor organoid lines from the mice and assessed the efficacy of autophagy inhibitors in overcoming Enzalutamide resistance in the tumor organoid model. We also investigated the impact ofTP53re‐expression in modulating responses to autophagy inhibitors using LNCaP cell line, which harbored aTP53missense mutation. Lastly, we attempted to identify potential autophagy‐related genes that were crucial forTP53‐deficient tumor maintenance.ResultsTP53loss‐of‐function was associated with increased levels of autophagy‐related proteins in aggressive prostate cancers andTrp53‐deleted genetically‐engineered mouse‐derived tumors. Moreover, the generated androgen receptor‐independent tumor organoids were highly vulnerable to autophagy inhibition. UponTP53re‐expression, not only did the surviving LNCaP cells demonstrate resistance, but they also showed growth advantage in response to autophagy inhibition. Lastly,PEX14, an important peroxisomal regulator was differentially upregulated in aggressive tumors withTP53loss‐of‐function mutations, thus implying the importance of peroxisome turnover in this tumor subtype.ConclusionOur results support the potential use of autophagy inhibitors in prostate cancers that containTP53loss‐of‐function mutations.