Oxidized LDL receptor 1 (OLR1) as a possible link between obesity, dyslipidemia and cancer

Magomed Khaidakov, Sona Mitra, Bum Yong Kang, Xianwei Wang, Susan Kadlubar, Giuseppe Novelli, Vinay Raj, Maria Winters, Weleetka C. Carter, Jawahar L. Mehta

Research output: Contribution to journalArticle

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Abstract

Recent studies have linked expression of lectin-like ox-LDL receptor 1 (OLR1) to tumorigenesis. We analyzed microarray data from Olr1 knockout (KO) and wild type (WT) mice for genes involved in cellular transformation and evaluated effects of OLR1 over-expression in normal mammary epithelial cells (MCF10A) and breast cancer cells (HCC1143) in terms of gene expression, migration, adhesion and transendothelial migration. Twenty-six out of 238 genes were inhibited in tissues of OLR1 KO mice; the vast majority of OLR1 sensitive genes contained NF-κB binding sites in their promoters. Further studies revealed broad inhibition of NF-kB target genes outside of the transformation-associated gene pool, with enrichment themes of defense response, immune response, apoptosis, proliferation, and wound healing. Transcriptome of Olr1 KO mice also revealed inhibition of de novo lipogenesis, rate-limiting enzymes fatty acid synthase (Fasn), stearoyl-CoA desaturase (Scd1) and ELOVL family member 6 (Elovl6), as well as lipolytic phospholipase A2 group IVB (Pla2g4b). In studies comparing MCF10A and HCC1143, the latter displayed 60% higher OLR1 expression. Forced over-expression of OLR1 resulted in upregulation of NF-κB (p65) and its target pro-oncogenes involved in inhibition of apoptosis (BCL2, BCL2A1, TNFAIP3) and regulation of cell cycle (CCND2) in both cell lines. Basal expression of FASN, SCD1 and PLA2G4B, as well as lipogenesis transcription factors PPARA, SREBF2 and CREM, was higher in HCC1143 cells. Over-expression of OLR1 in HCC1143 cells also enhanced cell migration, without affecting their adherence to TNFα-activated endothelium or transendothelial migration. On the other hand, OLR1 neutralizing antibody inhibited both adhesion and transmigration of untreated HCC1143 cells. We conclude that OLR1 may act as an oncogene by activation of NF-kB target genes responsible for proliferation, migration and inhibition of apoptosis and de novo lipogenesis genes.

Original languageEnglish
Article numbere20277
JournalPLoS One
Volume6
Issue number5
DOIs
Publication statusPublished - 2011

Fingerprint

Oxidized LDL Receptors
hyperlipidemia
Dyslipidemias
LDL Lipoproteins
obesity
Obesity
receptors
neoplasms
Genes
Neoplasms
Lipogenesis
lipogenesis
Knockout Mice
Transendothelial and Transepithelial Migration
transcription factor NF-kappa B
genes
apoptosis
NF-kappa B
oncogenes
Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Khaidakov, M., Mitra, S., Kang, B. Y., Wang, X., Kadlubar, S., Novelli, G., ... Mehta, J. L. (2011). Oxidized LDL receptor 1 (OLR1) as a possible link between obesity, dyslipidemia and cancer. PLoS One, 6(5), [e20277]. https://doi.org/10.1371/journal.pone.0020277

Oxidized LDL receptor 1 (OLR1) as a possible link between obesity, dyslipidemia and cancer. / Khaidakov, Magomed; Mitra, Sona; Kang, Bum Yong; Wang, Xianwei; Kadlubar, Susan; Novelli, Giuseppe; Raj, Vinay; Winters, Maria; Carter, Weleetka C.; Mehta, Jawahar L.

In: PLoS One, Vol. 6, No. 5, e20277, 2011.

Research output: Contribution to journalArticle

Khaidakov, M, Mitra, S, Kang, BY, Wang, X, Kadlubar, S, Novelli, G, Raj, V, Winters, M, Carter, WC & Mehta, JL 2011, 'Oxidized LDL receptor 1 (OLR1) as a possible link between obesity, dyslipidemia and cancer', PLoS One, vol. 6, no. 5, e20277. https://doi.org/10.1371/journal.pone.0020277
Khaidakov, Magomed ; Mitra, Sona ; Kang, Bum Yong ; Wang, Xianwei ; Kadlubar, Susan ; Novelli, Giuseppe ; Raj, Vinay ; Winters, Maria ; Carter, Weleetka C. ; Mehta, Jawahar L. / Oxidized LDL receptor 1 (OLR1) as a possible link between obesity, dyslipidemia and cancer. In: PLoS One. 2011 ; Vol. 6, No. 5.
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