LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump
LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump
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DOI：
10.1038/onc.2012.183
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发表时间：
2013-03-28
期刊：
影响因子：
8
通讯作者：
Qin, W.
中科院分区：
文献类型：
--
作者：
Fan, S.;Niu, Y.;Qin, W.
在肿瘤治疗过程中要克服的一个主要障碍是对化疗的耐药性;新兴的研究表明，导致这一问题的一个关键因素是酸性肿瘤微环境。在此，我们发现LASS 2在耐药的密歇根癌症基金会-7/阿霉素（MCF-7/ADR）人乳腺癌细胞中的表达显著低于药物敏感的MCF-7细胞，并且LASS 2的低表达与乳腺癌患者的不良预后相关。我们的研究结果表明，LASS 2在MCF-7/ADR细胞中的过表达增加了对多种化疗药物的化疗敏感性，包括阿霉素（Dox），而LASS 2在MCF-7细胞中的敲低降低了化疗敏感性。细胞周期分析显示，在LASS 2过表达的细胞Dox暴露后，凋亡相应增加，表明LASS 2的过表达增加了对Dox细胞毒性的敏感性。这种作用是由pH（e）（细胞外pH）和溶酶体pH的显著增加介导的，并且更多的Dox进入细胞并停留在细胞核中。在裸鼠中，LASS 2过表达和Dox的组合显著抑制异种移植物的生长。我们的研究结果表明，LASS 2参与化疗的结果和低LASS 2表达可能预测化疗耐药性。Oncogene（2013）32，1682-1690; doi：10.1038/onc.2012.183; 2012年5月14日在线发表
A main obstacle to overcome during the treatment of tumors is drug resistance to chemotherapy; emerging studies indicate that a key factor contributing to this problem is the acidic tumor microenvironment. Here, we found that LASS2 expression was significantly lower in drug-resistant Michigan Cancer Foundation-7/adriamycin (MCF-7/ADR) human breast cancer cells than the drug-sensitive MCF-7 cells, and low expression of LASS2 was associated with poor prognosis in patients with breast cancer. Our results showed that the overexpression of LASS2 in MCF-7/ADR cells increased the chemosensitivity to multiple chemotherapeutic agents, including doxorubicin (Dox), whereas LASS2 knockdown in MCF-7 cells decreased the chemosensitivity. Cell-cycle analysis revealed a corresponding increase in apoptosis in the LASS2-overexpressing cells following Dox exposure, showing that the overexpression of LASS2 increased the susceptibility to Dox cytotoxicity. This effect was mediated by a significant increase in pH(e) (extracellular pH) and lysosomal pH, and more Dox entered the cells and stayed in the nuclei of cells. In nude mice, the combination of LASS2 overexpression and Dox significantly inhibited the growth of xenografts. Our findings suggest that LASS2 is involved in chemotherapeutic outcomes and low LASS2 expression may predict chemoresistance. Oncogene ( 2013) 32, 1682-1690; doi:10.1038/onc.2012.183; published online 14 May 2012