ABCA2 transporter deficiency reduces incidence of TRAMP prostate tumor metastasis and cellular chemotactic migration.
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.
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, 29425, United States.
Jody T
JT
Mack
Kristi L
KL
Helke
Gabrielle
G
Normand
CoDanielle
C
Green
Danyelle M
DM
Townsend
Kenneth D
KD
Tew
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018528:ATP-Binding Cassette Transporters; C498824:Abca2 protein, mouse