Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide-chlorambucil conjugate.
Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide-chlorambucil conjugate.
复制标题
使用新型聚酰胺-苯丁酸氮芥偶联物靶向Xp11.2易位肾细胞癌的化疗耐药性
作者：
涉及TFE 3基因的Xp11.2易位的肾细胞癌（TFE 3-RCC）是最近发现的具有独特形态和临床表现的RCC亚组。通过Xp11.2易位产生的嵌合PRCC-TFE 3蛋白已被证明转录激活其下游靶基因，这些靶基因在TFE 3-RCC的致癌和肿瘤发展中起重要作用。然而，潜在的分子机制仍然知之甚少。在这里，我们表明在TFE 3-RCC细胞中，PRCC-TFE 3控制血红素加氧酶1（HMOX 1）表达以赋予化学抗性。HMOX 1的抑制使PRCC-TFE 3表达细胞对遗传毒性试剂敏感。我们筛选了一种新的苯丁酸氮芥-聚酰胺缀合物（Chb），以靶向PRCC-TFE 3依赖性转录，并将Chb 16鉴定为HMOX 1表达的PRCC-TFE 3依赖性转录抑制剂。用Chb 16处理患者来源的癌细胞表现出衰老和生长停滞，并且TFE 3-RCC细胞对遗传毒性试剂依托泊苷的敏感性增加。因此，我们的数据表明，TFE 3-RCC细胞通过HMOX 1表达获得化学抗性，Chb 16抑制HMOX 1可能是TFE 3-RCC的有效治疗策略。PRCC-TFE 3调节血红素加氧酶1（HMOX 1）的表达并赋予Xp11.2易位肾细胞癌对化疗的抗性。一种新的苯丁酸氮芥-聚酰胺缀合物Chb 16靶向PRCC-TFE 3依赖性转录，诱导衰老和生长停滞，并增加TFE 3-RCC细胞对遗传毒性药物的敏感性。
Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3‐RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC‐TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3‐RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3‐RCC cells, PRCC‐TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC‐TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil–polyamide conjugate (Chb) to target PRCC‐TFE3‐dependent transcription, and identified Chb16 as a PRCC‐TFE3‐dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient‐derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3‐RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3‐RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3‐RCC. PRCC‐TFE3 regulates the expression of heme oxygenase 1 (HMOX1) and confers resistance to chemotherapy in Xp11.2 translocated renal cell carcinoma. A novel chlorambucil–polyamide conjugate, Chb 16, targets PRCC‐TFE3‐dependent transcription, induces senescence and growth arrest, and increases the sensitivity of TFE3‐RCC cells to genotoxic drugs.
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影响因子：
3.3
作者：
Freund A;Laberge RM;Demaria M;Campisi J
通讯作者：
Campisi J
DOI：
10.1158/1078-0432.ccr-18-0269
发表时间：
2018-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Damayanti NP;Budka JA;Khella HWZ;Ferris MW;Ku SY;Kauffman E;Wood AC;Ahmed K;Chintala VN;Adelaiye-Ogala R;Elbanna M;Orillion A;Chintala S;Kao C;Linehan WM;Yousef GM;Hollenhorst PC;Pili R
通讯作者：
Pili R
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
7.7
作者：
Jeong, Eutteum;Brady, Owen A.;Puertollano, Rosa
通讯作者：
Puertollano, Rosa
影响因子：
4.8
作者：
Ishiguro, Naoko;Yoshida, Haruhiko
通讯作者：
Yoshida, Haruhiko