期刊
CANCER LETTERS
卷 300, 期 2, 页码 154-161出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2010.09.017
关键词
TRAMP; ABC transporter; Prostate; Chemotaxis; Metastasis
类别
资金
- Ruth L Kirschstein NRSA Fellowship [CA117749]
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 epithelialmesenchymal 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 (MD) 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 003 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
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