PMID- 21041019 OWN - NLM STAT- MEDLINE DCOM- 20110106 LR - 20211020 IS - 1872-7980 (Electronic) IS - 0304-3835 (Print) IS - 0304-3835 (Linking) VI - 300 IP - 2 DP - 2011 Jan 28 TI - ABCA2 transporter deficiency reduces incidence of TRAMP prostate tumor metastasis and cellular chemotactic migration. PG - 154-61 LID - 10.1016/j.canlet.2010.09.017 [doi] AB - 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. CI - Published by Elsevier Ireland Ltd. FAU - Mack, Jody T AU - Mack JT AD - Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, 29425, United States. FAU - Helke, Kristi L AU - Helke KL FAU - Normand, Gabrielle AU - Normand G FAU - Green, CoDanielle AU - Green C FAU - Townsend, Danyelle M AU - Townsend DM FAU - Tew, Kenneth D AU - Tew KD LA - eng GR - F32 CA117749/CA/NCI NIH HHS/United States GR - R01 CA085660/CA/NCI NIH HHS/United States GR - CA117749/CA/NCI NIH HHS/United States GR - T32 CA119945/CA/NCI NIH HHS/United States GR - R01 CA085660-13/CA/NCI NIH HHS/United States GR - T32 CA119945-05/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20101030 PL - Ireland TA - Cancer Lett JT - Cancer letters JID - 7600053 RN - 0 (ATP-Binding Cassette Transporters) RN - 0 (Abca2 protein, mouse) SB - IM MH - ATP-Binding Cassette Transporters/*metabolism MH - Adenocarcinoma/*metabolism/pathology MH - Animals MH - Cell Movement/*physiology MH - Immunohistochemistry MH - Magnetic Resonance Imaging MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Transgenic MH - Neoplasm Invasiveness/pathology MH - Prostatic Neoplasms/*metabolism/pathology MH - Reverse Transcriptase Polymerase Chain Reaction PMC - PMC2994978 MID - NIHMS245107 EDAT- 2010/11/03 06:00 MHDA- 2011/01/07 06:00 PMCR- 2012/01/28 CRDT- 2010/11/03 06:00 PHST- 2010/08/17 00:00 [received] PHST- 2010/09/15 00:00 [accepted] PHST- 2010/11/03 06:00 [entrez] PHST- 2010/11/03 06:00 [pubmed] PHST- 2011/01/07 06:00 [medline] PHST- 2012/01/28 00:00 [pmc-release] AID - S0304-3835(10)00462-3 [pii] AID - 10.1016/j.canlet.2010.09.017 [doi] PST - ppublish SO - Cancer Lett. 2011 Jan 28;300(2):154-61. doi: 10.1016/j.canlet.2010.09.017. Epub 2010 Oct 30.