Loss of an ABC transporter in Arabidopsis thaliana confers hypersensitivity to the anti-cancer drug bleomycin
Loss of an ABC transporter in Arabidopsis thaliana confers hypersensitivity to the anti-cancer drug bleomycin
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拟南芥中 ABC 转运蛋白的缺失导致对抗癌药物博莱霉素过敏
DOI：
10.1016/j.dnarep.2021.103174
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发表时间：
2021-07-10
期刊：
影响因子：
3.8
通讯作者：
Wang, Lili
中科院分区：
文献类型：
--
作者：
Li, Tong;Xu, Shijun;Wang, Lili
博来霉素（BLM）是临床上常用的抗癌药物。然而，一些癌细胞对BLM具有耐药性，这限制了BLM在化疗中的应用。但人们对这种耐药性的潜在机制知之甚少。在这里，我们证明了ATP结合盒（ABC）转运体ABCC3是拟南芥抗性所必需的。在ddrm （DNA损伤反应突变体）的基因筛选中，我们发现ABCC3的缺失导致了对BLM的超敏反应。相比之下，ABCC3的过表达增强了对BLM的抗性。我们进一步发现ABCC3的表达是由BLM诱导的，它依赖于蛋白激酶ATM和转录因子SOG1，这是DNA损伤反应的两个主要调节因子。我们的研究发现ABC转运蛋白参与了BLM的耐药，这表明ABC转运蛋白抑制剂与BLM联合使用可能会提高BLM在癌症治疗中的疗效。
Bleomycin (BLM) is used as an anti-cancer drug clinically. However, some cancer cells are resistant to BLM, which limits the usage of BLM in chemotherapy. But the underlying mechanism of such resistance is poorly understood. Here we show that the ATP binding cassette (ABC) transporter ABCC3 is required for the BLMresistance in Arabidopsis. In a genetic screen for ddrm (DNA damage response mutants), we found that loss of ABCC3 confers the hypersensitivity to BLM. In contrast, overexpression of ABCC3 enhances the resistance to BLM. We further found that the expression of ABCC3 is induced by BLM, which is dependent on the protein kinase ATM and the transcription factor SOG1, two master regulators of DNA damage response. Our study revealed that the ABC transporter contributes to BLM-resistance, indicating that the combination of ABC transporter inhibitors and BLM may enhance the efficacy of BLM in cancer therapy.