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Control of metabolic genes in human mammary epithelial cells by vitamin D hinders adaptation to glutamine deprivation
Author(s) -
Beaudin Sarah,
Welsh JoEllen
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.639.24
Subject(s) - glutamine , glutamine synthetase , glutaminase , calcitriol receptor , biology , microbiology and biotechnology , cancer research , receptor , biochemistry , amino acid
The metabolic switch associated with cancer progression increases cellular requirements for nutrients, including the amino acid glutamine. The p53 tumor suppressor has been shown to abrogate the metabolic switch via effects on glutamine metabolism. Through microarray profiling of human mammary epithelial cells (HMEC) treated with 1,25‐dihydroxyvitamin D (1,25D) we discovered that the vitamin D receptor also targets genes involved in glutamine metabolism. qPCR assays in immortalized HMECs confirmed that 1,25D increased (>;10‐fold) the glutamate transporter SLC1A1 and reduced (>;4‐fold) the glutamine synthetase GLUL. Western blotting demonstrated decreased expression of glutamine synthetase (GS) and increased expression of SLC1A1 following 1,25D treatment. Because GS is essential for proliferation during glutamine depletion, we hypothesized that its inhibition by 1,25D would interfere with adaptation to low glutamine. Indeed, HMECs pretreated with 1,25D failed to adapt to glutamine deprivation, and high extracellular glutamine partially rescued 1,25D‐mediated growth arrest. Similar 1,25D‐mediated changes in GLUL and SLC1A1 were observed in pre‐neoplastic HMECs expressing SV40, but not in tumorigenic HMECs expressing SV40 and oncogenic ras. Collectively, these data implicate VDR in regulation of a critical node of the cancer‐associated metabolic switch. Grant number: R21CA166434