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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acids / antagonists & inhibitors
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Acids / pharmacology
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Breast Neoplasms / diagnosis
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology
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Carcinoma / diagnosis
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Carcinoma / drug therapy
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Carcinoma / genetics*
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Carcinoma / pathology
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Cell Line, Tumor
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Doxorubicin / administration & dosage
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Doxorubicin / pharmacology
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Doxorubicin / therapeutic use
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics*
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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HEK293 Cells
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Humans
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Hydrogen-Ion Concentration / drug effects
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Mice
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Mice, Nude
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Prognosis
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Sphingosine N-Acyltransferase / genetics
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Sphingosine N-Acyltransferase / physiology*
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Tumor Microenvironment* / drug effects
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Tumor Microenvironment* / genetics
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology*
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Vacuolar Proton-Translocating ATPases / antagonists & inhibitors*
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Vacuolar Proton-Translocating ATPases / genetics
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Vacuolar Proton-Translocating ATPases / metabolism
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Xenograft Model Antitumor Assays
Substances
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Acids
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Antineoplastic Agents
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Enzyme Inhibitors
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Membrane Proteins
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Tumor Suppressor Proteins
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Doxorubicin
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CERS2 protein, human
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Sphingosine N-Acyltransferase
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Vacuolar Proton-Translocating ATPases