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Anticancer Res. 2002 Jul-Aug;22(4):1933-41.

Overexpression of human phosphoglycerate kinase 1 (PGK1) induces a multidrug resistance phenotype.

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  • 1Department of Hematology/Oncology, Massachusetts General Hospital, Boston 02114, USA.

Abstract

BACKGROUND:

Multidrug resistance is a significant barrier to the development of successful cancer treatment. To identify genetic alterations that are directly involved in paclitaxel resistance, a functional cloning strategy was developed.

MATERIALS AND METHODS:

Using mRNA from paclitaxel resistant human ovarian cancer cell line SW626TR, a cDNA library was established in a pCMV-Script vector that permits expression of cDNA inserts in mammalian cells. Transfection of the pCMV-Script/SW626TR cDNA library into the paclitaxel-sensitive human osteogenic sarcoma cell line, U-20S, resulted in several paclitaxel-resistant clones.

RESULTS:

DNA sequencing of clone C16 demonstrates complete homology to human phosphoglycerate kinase 1 (PGK1). Retransfection of the PGK1 insert into U-20S confers a multidrug resistant phenotype, characterized by a 30-fold increase in paclitaxel resistance, and cross-resistance to vincristine; adriamycin and mitoxantrone, but not methotrexate or cisplatin. Enzymatic analysis of the PGK1 transfectants demonstrates an increase in PGK1 activity as compared to the parental cell line, U-20S. Northern and Western analysis of PGK1 transfectants reveals no change in MDR-1 expression compared with the parental cell line. In addition, co-culture of PGK1 transfectants with verapamil only partially reverses the multidrug resistant phenotype. Rhodamine 123 studies are also consistent with an MDR-1 independent mechanism of increased drug efflux.

CONCLUSION:

Together this data suggests that PGK1 can induce a multidrug resistant phenotype through an MDR-1 independent mechanism.

PMID:
12174867
[PubMed - indexed for MEDLINE]
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