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LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump

Oncogene volume 32, pages 1682–1690 (2013)Cite this article

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Abstract

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 pHe (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.

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Accession codes

Accessions

Gene Expression Omnibus

Abbreviations

5-FU:

5-fluorouracil

ABC:

ATP-binding cassette

ADR:

adriamycin

DDP:

cisplatin

DFS:

disease-free survival

Dox:

doxorubicin

EPI:

epirubicin hydrochloride

IAP:

inhibitor of apoptosis protein

LASS2:

Homo sapiens longevity assurance homolog 2 of yeast LAG1

MDR:

multidrug resistance

MTO:

mitoxantrone dihydrochloride

OS:

overall survival

pHe:

extracellular pH

pHi:

intracellular pH

PSS:

protonation, sequestration and secretion

V-ATPase:

vacuolar-H+-ATPase

VRL:

vinorelbine bitartrate

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Acknowledgements

We are grateful to Shenglin Huang, Jun Li and Jie Chen for the kind suggestions and technical assistance. This work was supported by grants from the National Key Basic Research Program of China (2009CB521803), National Key Sci-Tech Special Project of China (2012ZX10002011-004) and National Natural Science Foundation of China (30973492 and 81030038).

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  1. S Fan and Y Niu: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    S Fan, Y Niu, Z Wu, H You, R Ke, J Song, Q Shen, W Wang, G Yao, H Shu, H Lin, Z Zhang, J Gu & W Qin

  2. Department of Biotechnology, School of Life Science, Jiangsu Normal University, Xuzhou, China

    S Fan

  3. Key Laboratory of Medical Molecular Diagnosis, Guangdong Medical College, Guangdong, China

    N Tan

  4. Department of Oncology, The Affiliated City Hospital of Xuzhou Medical College, Xuzhou, China

    Y Wang

  5. Department of Experimental Pathology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    M Yao

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Fan, S., Niu, Y., Tan, N. et al. LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump. Oncogene 32, 1682–1690 (2013). https://doi.org/10.1038/onc.2012.183

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