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LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump.
- Source :
-
Oncogene [Oncogene] 2013 Mar 28; Vol. 32 (13), pp. 1682-90. Date of Electronic Publication: 2012 May 14. - Publication Year :
- 2013
-
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.
- Subjects :
- Acids antagonists & inhibitors
Acids pharmacology
Animals
Antineoplastic Agents administration & dosage
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Breast Neoplasms diagnosis
Breast Neoplasms drug therapy
Breast Neoplasms pathology
Carcinoma diagnosis
Carcinoma drug therapy
Carcinoma pathology
Cell Line, Tumor
Doxorubicin administration & dosage
Doxorubicin pharmacology
Doxorubicin therapeutic use
Drug Resistance, Neoplasm drug effects
Enzyme Activation drug effects
Enzyme Activation genetics
Enzyme Inhibitors metabolism
Enzyme Inhibitors pharmacology
Female
Gene Expression Regulation, Neoplastic drug effects
HEK293 Cells
Humans
Hydrogen-Ion Concentration drug effects
Membrane Proteins genetics
Mice
Mice, Nude
Prognosis
Sphingosine N-Acyltransferase genetics
Tumor Suppressor Proteins genetics
Vacuolar Proton-Translocating ATPases genetics
Vacuolar Proton-Translocating ATPases metabolism
Xenograft Model Antitumor Assays
Breast Neoplasms genetics
Carcinoma genetics
Drug Resistance, Neoplasm genetics
Membrane Proteins physiology
Sphingosine N-Acyltransferase physiology
Tumor Microenvironment drug effects
Tumor Microenvironment genetics
Tumor Suppressor Proteins physiology
Vacuolar Proton-Translocating ATPases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 32
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 22580606
- Full Text :
- https://doi.org/10.1038/onc.2012.183