Human UDP-Glucuronosyltransferases: Effects of altered expression in breast and pancreatic cancer cell lines

Centdrika Dates, Tariq Fahmi, Sebastian Pyrek, Aiwei Yao-Borengasser, Barbara Borowa-Mazgaj, Stacie Bratton, Susan Kadlubar, Peter Mackenzie, Randy Haun, A Radominska-Pandya

    Research output: Contribution to journalArticlepeer-review

    14 Citations (Scopus)

    Abstract

    Increased aerobic glycolysis and de novo lipid biosynthesis are common characteristics of invasive cancers. UDP-glucuronosyltransferases (UGTs) are phase II drug metabolizing enzymes that in normal cells possess the ability to glucuronidate these lipids and speed their excretion; however, de-regulation of these enzymes in cancer cells can lead to an accumulation of bioactive lipids, which further fuels cancer progression. We hypothesize that UGT2B isoform expression is down-regulated in cancer cells and that exogenous re-introduction of these enzymes will reduce lipid content, change the cellular phenotype, and inhibit cancer cell proliferation. In this study, steady-state mRNA levels of UGT isoforms from the 2B family were measured using qPCR in 4 breast cancer and 5 pancreatic cancer cell lines. Expression plasmids for UGT2B isoforms known to glucuronidate cellular lipids, UGT2B4, 2B7, and 2B15 were transfected into MCF-7 and Panc-1 cells, and the cytotoxic effects of these enzymes were analyzed using trypan blue exclusion, annexin V/PI staining, TUNEL assays, and caspase-3 immunohistochemistry. There was a significant decrease in cell proliferation and a significant increase in the number of dead cells after transfection with each of the 3 UGT isoforms in both cell lines. Cellular lipids were also found to be significantly decreased after transfection. The results presented here support our hypothesis and emphasize the important role UGTs can play in cellular proliferation and lipid homeostasis. Evaluating the effect of UGT expression on the lipid levels in cancer cell lines can be relevant to understanding the complex regulation of cancer cells, identifying the roles of UGTs as “lipid-controllers” in cellular homeostasis, and illustrating their suitability as targets for future clinical therapy development.

    Original languageEnglish
    Pages (from-to)714-723
    Number of pages10
    JournalCancer Biology and Therapy
    Volume16
    Issue number5
    DOIs
    Publication statusPublished - 1 Jan 2015

    Keywords

    • Breast cancer
    • MCF-7
    • Panc-1
    • Pancreatic cancer
    • UDP-glucuronosyltransferases

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