Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia.
JCI Insight. 2019 Feb 26;5(6):124092. doi: 10.1172/jci.insight.124092.
Anthracyclines are amongst the most effective chemotherapeutics ever developed, but they produce grueling side-effects, serious adverse events and resistance often develops over time. We found that these compounds can be sequestered by secreted cellular Prion protein (PrPC), blocking their cytotoxic activity. This effect was dose-dependent using either cell line-conditioned medium or human serum as a source of PrPC. Genetic depletion of PrPC or inhibition of binding via chelation of ionic copper prevented the interaction and restored cytotoxic activity. This was more pronounced for doxorubicin than its epimer, epirubicin. Investigating the relevance to breast cancer management, we found that the levels of PRNP transcript in pre-treatment tumor biopsies stratified relapse-free survival after neoadjuvant treatment with anthracyclines, particularly amongst doxorubicin-treated patients with residual disease at surgery (p=2.8E-08). These data suggest that local sequestration could mediate treatment resistance. Consistent with this, tumor cell expression of PrPC protein correlated with poorer response to doxorubicin but not epirubicin in an independent cohort analyzed by immunohistochemistry, particularly soluble isoforms released into the extracellular environment by shedding (p=0.015). These findings have important potential clinical implications for frontline regimen decision-making. We suggest there is warranted utility for prognostic PrPC/PRNP assays to guide chemo-sensitization strategies that exploit an understanding of PrPC-anthracycline-copper ion complexes.
蒽环类抗生素是迄今为止开发的最有效的化疗药物之一，但它们会产生严重的副作用和不良事件，而且随着时间的推移，往往会产生耐药性。我们发现，这些化合物可以被细胞分泌的朊病毒蛋白（PrPC）隔离，从而阻断其细胞毒性活性。无论是使用细胞系条件培养基还是人血清作为 PrPC 的来源，这种效应都是剂量依赖性的。通过螯合离子铜来耗尽 PrPC 或抑制其结合可以阻止这种相互作用并恢复细胞毒性活性。与表阿霉素相比，这种效应在阿霉素中更为明显。在研究其与乳腺癌管理的相关性时，我们发现，在接受蒽环类药物新辅助治疗后，PRNP 转录本在治疗前肿瘤活检中的水平可分层无复发生存率，尤其是在接受阿霉素治疗且手术时仍有残留疾病的患者中（p=2.8E-08）。这些数据表明，局部隔离可能介导治疗耐药性。通过免疫组织化学分析独立队列中的数据，与表阿霉素相比，肿瘤细胞中 PrPC 蛋白的表达与对阿霉素的反应较差相关，但与表阿霉素无关，尤其是通过脱落释放到细胞外环境中的可溶性同工型（p=0.015）。这些发现对一线治疗方案的决策具有重要的潜在临床意义。我们建议，有必要利用预后 PrPC/PRNP 检测来指导化疗增敏策略，这些策略利用了对 PrPC-蒽环类药物-铜离子复合物的理解。
