ROR1通过调节药物外排泵ABCB1来调节乳腺癌的化学耐药性。,Scientific Reports

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ROR1通过调节药物外排泵ABCB1来调节乳腺癌的化学耐药性。
Scientific Reports ( IF 3.8 ) Pub Date : 2020-02-04 , DOI: 10.1038/s41598-020-58864-0
Norman Fultang ₁ , Abhinav Illendula ₁ , Jianhuang Lin ₂ , Manoj K Pandey ₃ , Zachary Klase ₁ , Bela Peethambaran ₁

Affiliation

化学抗性是乳腺癌（BC）死亡的主要原因之一。为了对抗BC的化学抗性，了解调节化学抗性的分子至关重要。药物外排泵ABCB1在耐化学性肿瘤中过表达，在那里它从细胞中排出各种化学治疗剂。由于它在正常细胞和癌细胞中均表达，因此直接靶向ABCB1的尝试由于低特异性和正常组织的破坏而失败。提议的抑制ABCB1的方法是针对其癌症特异性上游调节剂，以减轻对正常组织的损害。很少有这类癌症特异性上游调节剂被描述。在这里，我们将ROR1表征为ABCB1的上游调节剂。ROR1在发育过程中高表达，但在正常成人组织中不表达。然而，它在几种癌症中高度表达。ROR1在耐化学性BC中过表达，与不良的治疗反应和肿瘤复发相关。我们的数据表明，ROR1抑制使BC细胞对化学药物敏感。我们还显示ROR1通过MAPK / ERK和p53调节ABCB1稳定性和转录。验证我们的总体发现，ROR1的抑制与化学药物从细胞中流出的减少直接相关。总体而言，我们的结果突出了ROR1作为多药耐药性恶性肿瘤治疗靶点的潜力。验证我们的总体发现，ROR1的抑制与化学药物从细胞中流出的减少直接相关。总体而言，我们的结果突出了ROR1作为多药耐药性恶性肿瘤治疗靶点的潜力。验证我们的总体发现，ROR1的抑制与化学药物从细胞中流出的减少直接相关。总体而言，我们的结果突出了ROR1作为多药耐药性恶性肿瘤治疗靶点的潜力。

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ROR1 regulates chemoresistance in Breast Cancer via modulation of drug efflux pump ABCB1.

Chemoresistance is one of the leading causes of mortality in breast cancer (BC). Understanding the molecules regulating chemoresistance is critical in order to combat chemoresistant BC. Drug efflux pump ABCB1 is overexpressed in chemoresistant neoplasms where it effluxes various chemotherapeutic agents from cells. Because it is expressed in normal and cancerous cells alike, attempts at targeting ABCB1 directly have failed due to low specificity and disruption of normal tissue. A proposed method to inhibit ABCB1 is to target its cancer-specific, upstream regulators, mitigating damage to normal tissue. Few such cancer-specific upstream regulators have been described. Here we characterize ROR1 as an upstream regulator of ABCB1. ROR1 is highly expressed during development but not expressed in normal adult tissue. It is however highly expressed in several cancers. ROR1 is overexpressed in chemoresistant BC where it correlates with poor therapy response and tumor recurrence. Our data suggests, ROR1 inhibition sensitizes BC cells to chemo drugs. We also show ROR1 regulates ABCB1 stability and transcription via MAPK/ERK and p53. Validating our overall findings, inhibition of ROR1 directly correlated with decreased efflux of chemo-drugs from cells. Overall, our results highlight ROR1's potential as a therapeutic target for multidrug resistant malignancies.

更新日期：2020-02-04

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