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Cancer Lett. 2011 Jan 28;300(2):154-61. doi: 10.1016/j.canlet.2010.09.017. Epub 2010 Oct 30.

ABCA2 transporter deficiency reduces incidence of TRAMP prostate tumor metastasis and cellular chemotactic migration.

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  • 1Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, 29425, United States.

Abstract

In order to study the effects of ATP-binding cassette transporter 2 (ABCA2) deficiency on the progression of prostate cancer, congenic Abca2 knockout (KO) mice were crossed to the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. ABCA2 expression was elevated in wild-type/TRAMP (WT/Tg) dorsal prostate, a region comprising the most aggressive tumors in this model, compared to non-transgenic WT mice. Primary prostate tumor progression was similar in KO/Tg and WT/Tg mice with respect to pathological score, prostate tumor growth, as calculated using MRI volumetry, and proliferative index, as determined by PCNA immunostaining. Vimentin, a marker of the epithelial-mesenchymal transition, was expressed at similar levels in prostate, but elevated in histologically normal seminal vesicles (SV) in KO/Tg mice (P < 0.02), concomitant with an increased SV volume (P < 0.01). These changes in the SV did not exacerbate the metastatic phenotype of this disease model; rather, KO/Tg mice aged 20-25 weeks had no detectable metastases while 38% of WT/Tg developed metastases to lung and/or lymph nodes. The absence of a metastatic phenotype in KO/Tg mice was reprised in stable ABCA2 knockdown (KD) cells where chemotactic, but not random, migration was impaired (P = 0.0004). Expression levels of sphingolipid biosynthetic enzymes were examined due to the established link of the transporter with sphingolipid homeostasis. Galactosylceramide synthase (GalCerS) mRNA levels were over 8-fold higher in KD cells (P = 0.001), while lactosylceramide synthase (LacCerS) and CTP:choline cytidylyltransferase (CCT) were significantly reduced (P < 0.0001 and 0.03, respectively). Overall, we demonstrate that ABCA2-deficiency inhibits prostate tumor metastasis in vivo and decreases chemotactic potential of cells, conceivably due to altered sphingolipid metabolism.

Published by Elsevier Ireland Ltd.

PMID:
21041019
[PubMed - indexed for MEDLINE]
PMCID:
PMC2994978
Free PMC Article
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