Targeting CXCR1 and CXCR2 to overcome radiotherapy resistance in PTEN-deficient prostate carcinoma
Targeting CXCR1 and CXCR2 to overcome radiotherapy resistance in PTEN-deficient prostate carcinoma
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靶向 CXCR1 和 CXCR2 以克服 PTEN 缺陷型前列腺癌的放疗耐药性
DOI：
10.1101/2020.03.16.993394
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Armstrong C
中科院分区：
文献类型：
--
作者：
Armstrong C
肿瘤抑制蛋白pteni的功能障碍在原发性前列腺癌中很常见，并且与放疗后复发（RT）有关。临床前模型支持升高的cxc趋化因子信号作为pten耗竭的疾病进展和治疗耐药的关键介质。我们评估了pten缺乏与cxc趋化因子信号的相关性及其与临床结果的关系。基因表达分析表明，aPTENLOW/CXCR1HIGH/ cxcr2high肿瘤簇与较早的生化复发时间（HR分别为5.87和2.65）和系统性转移的发生（HR为3.51）相关。在体外，pten缺陷前列腺癌细胞暴露于电离辐射（IR）后，cxcl信号进一步扩增。在pten缺失的细胞模型中，抑制cxcr1 /2信号会增加ir敏感性。在体内，与对照或单独使用IR相比，使用cxcr1 /2靶向肽肽（x1/2pal-i3）或cxcr2特异性拮抗剂（AZD5069）联合缺乏IR topten的异种移植物可减轻肿瘤的生长和进展。尸检分析证实，给药x1/2pal-i3可减弱ir诱导的cxcl信号传导和抗凋亡蛋白表达。针对cxc趋化因子信号的干预措施可能为局部晚期和少转移性前列腺癌提供一种有效的联合放疗策略，这些前列腺癌通常存在pten缺陷灶。
Functional impairment of the tumour-suppressorPTENis common in primary-prostate cancer and has been linked to relapse post-radiotherapy (RT). Pre-clinical modelling supports elevated CXC-chemokine signaling as a critical mediator ofPTEN-depleted disease progression and therapeutic resistance. We assessed the correlation ofPTEN-deficiency with CXC-chemokine signaling and its association with clinical outcomes. Gene expression analysis characterized aPTENLOW/CXCR1HIGH/CXCR2HIGHcluster of tumors that associates with earlier time-to-biochemical recurrence (HR 5.87 and HR 2.65 respectively) and development of systemic metastasis (HR 3.51).In vitro, CXCL-signaling was further amplified following exposure ofPTEN-deficient prostate cancer cell lines to ionizing radiation (IR). Inhibition of CXCR1/2-signaling inPTEN-depleted cell-based models increased IR-sensitivity.In vivo, administration of a CXCR1/2-targeted pepducin (x1/2pal-i3), or CXCR2-specific antagonist (AZD5069), in combination with IR toPTEN-deficient xenografts attenuated tumor growth and progression compared to control or IR alone. Post-mortem analysis confirmed that x1/2pal-i3 administration attenuated IR-induced CXCL-signaling and anti-apoptotic protein expression. Interventions targeting CXC-chemokine signaling may provide an effective strategy to combine with radiotherapy, in both locally-advanced and oligometastatic-prostate cancers, with known presence ofPTEN-deficient foci.
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影响因子：
50.3
作者：
Taylor BS;Schultz N;Hieronymus H;Gopalan A;Xiao Y;Carver BS;Arora VK;Kaushik P;Cerami E;Reva B;Antipin Y;Mitsiades N;Landers T;Dolgalev I;Major JE;Wilson M;Socci ND;Lash AE;Heguy A;Eastham JA;Scher HI;Reuter VE;Scardino PT;Sander C;Sawyers CL;Gerald WL
通讯作者：
Gerald WL
影响因子：
8.8
作者：
Di Mitri, Diletta;Mirenda, Michela;Alimonti, Andrea
通讯作者：
Alimonti, Andrea
影响因子：
3.1
作者：
Singh S;Wu S;Varney M;Singh AP;Singh RK
通讯作者：
Singh RK
DOI：
10.1056/nejmoa1209978
发表时间：
2013-01-31
期刊：
The New England journal of medicine
影响因子：
--
作者：
Resnick MJ;Koyama T;Fan KH;Albertsen PC;Goodman M;Hamilton AS;Hoffman RM;Potosky AL;Stanford JL;Stroup AM;Van Horn RL;Penson DF
通讯作者：
Penson DF
DOI：
10.1016/s1470-2045(16)30102-4
发表时间：
2016-08
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Dearnaley D;Syndikus I;Mossop H;Khoo V;Birtle A;Bloomfield D;Graham J;Kirkbride P;Logue J;Malik Z;Money-Kyrle J;O'Sullivan JM;Panades M;Parker C;Patterson H;Scrase C;Staffurth J;Stockdale A;Tremlett J;Bidmead M;Mayles H;Naismith O;South C;Gao A;Cruickshank C;Hassan S;Pugh J;Griffin C;Hall E;CHHiP Investigators
通讯作者：
CHHiP Investigators