LASS2可通过抑制V-ATP酶质子泵而抵消酸性肿瘤微环境，进而增强乳腺癌的化学敏感性

State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Renji Hospital, No. 25/2200, Xietu Road, Shanghai 200032, China

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. © 2013 Macmillan Publishers Limited All rights reserved.

Qin, W.; State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Renji Hospital, No. 25/2200, Xietu Road, Shanghai 200032, China; email:wxqin@sjtu.edu.cn