Targeting HOX-PBX interactions causes death in oral potentially malignant and squamous carcinoma cells but not normal oral keratinocytes
Targeting HOX-PBX interactions causes death in oral potentially malignant and squamous carcinoma cells but not normal oral keratinocytes
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DOI：
10.1186/s12885-018-4622-0
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发表时间：
2018-07-06
期刊：
影响因子：
3.8
通讯作者：
Hunter, Keith D.
中科院分区：
文献类型：
--
作者：
Platais, Christopher;Radhakrishnan, Raghu;Hunter, Keith D.
背景：HOX基因在包括口腔鳞状细胞癌在内的许多癌症中都有高表达，并且这些基因的功能作用正在逐渐被了解。过度表达的模式表明抑制可能在治疗上是有用的。通过使用合成肽（如HXR9）抑制HOX蛋白与PBX辅助因子的结合，可导致多种癌症的细胞凋亡。方法：在永生化的正常口腔（NOK）、潜在恶性（PMOL）和鳞状细胞癌（OSCC）细胞中检测HOX-PBX抑制肽HXR9的活性，并与无活性肽CXR9进行比较。LDH法测定细胞毒性。采用qPCR和western blotting检测PBX1/2和c-Fos的表达。Annexin-V法检测细胞凋亡。结果：PMOL和OSCC细胞表达PBX1/2。HXR9对HOX-PBX的抑制可引起PMOL和OSCC细胞的死亡，而对NOKs细胞无抑制作用。HXR9处理导致部分细胞凋亡和c-Fos表达增加，而CXR9则没有。观察到HOX表达与HXR9抗性之间存在相关性。结论：抑制HOX-PBX相互作用可导致OSCC/PMOL选择性凋亡，提示选择性毒性，可能具有临床应用价值。
Background: High HOX gene expression has been described in many cancers, including oral squamous cell carcinoma and the functional roles of these genes are gradually being understood. The pattern of overexpression suggests that inhibition may be useful therapeutically. Inhibition of HOX protein binding to PBX cofactors by the use of synthetic peptides, such as HXR9, results in apoptosis in multiple cancers.Methods: Activity of the HOX-PBX inhibiting peptide HXR9 was tested in immortalised normal oral (NOK), potentially-malignant (PMOL) and squamous cell carcinoma (OSCC) cells, compared to the inactive peptide CXR9. Cytotoxicity was assessed by LDH assay. Expression of PBX1/2 and c-Fos was assessed by qPCR and western blotting. Apoptosis was assessed by Annexin-V assay.Results: PMOL and OSCC cells expressed PBX1/2. HOX-PBX inhibition by HXR9 caused death of PMOL and OSCC cells, but not NOKs. HXR9 treatment resulted in apoptosis and increased expression of c-Fos in some cells, whereas CXR9 did not. A correlation was observed between HOX expression and resistance to HXR9.Conclusion: Inhibition of HOX-PBX interactions causes selective apoptosis of OSCC/PMOL, indicating selective toxicity that may be useful clinically.