CYP24 splicing variants are associated with different patterns of constitutive and calcitriol-inducible CYP24 activity in human prostate cancer cell lines.
24-Hydroxylase (CYP24) activity modulates in vitro and in vivo calcitriol metabolism and biologic effects. We have investigated, in human PC3, DU145 and LNCaP prostate cancer cell lines, the relationship of CYP24 single nucleotide polymorphisms (SNPs) and splicing and the variable patterns of baseline and calcitriol-inducible CYP24 activity. DU145 cells exhibit baseline CYP24 activity that is further induced by calcitriol. Baseline and inducible CYP24 activity were barely detectable in LNCaP cells. In PC3, baseline CYP24 activity was undetectable but induced by calcitriol. A different pattern of SNPs was identified at positions 24, 46, 146 and 198 in the intron between exons 9 and 10 of CYP24 gene in each cancer cell line. DU145 displayed baseline CYP24 splicing between exon 9 and exon 11; splicing was only observed in calcitriol treated LNCaP cells. Untreated PC3 had a mixed picture (splicing and no splicing); only the spliced form was seen after calcitriol treatment. These results demonstrate that calcitriol treatment modulates CYP24 splicing, and suggests that differences in CYP24 splicing are associated with different patterns of CYP24 activity.
Muindi
Josephia R
JR
Department of Medicine, Roswell Park Cancer Institute, Elm and Carlson Streets, Buffalo, NY 14263, USA. josephia.muindi@roswellpark.org
Nganga
Alain
A
Engler
Kristie L
KL
Coignet
Lionel J
LJ
Johnson
Candace S
CS
Trump
Donald L
DL
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005091:Exons / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics*; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol