CYP24A1 splice variants--implications for the antitumorigenic actions of 1,25-(OH)2D3 in colorectal cancer.
25-hydroxyvitamin D3 24-hydroxylase (CYP24A1), the catabolizing enzyme of the active vitamin D3, is often overexpressed in solid tumors. The unbalanced high levels of CYP24A1 seem to be a determinant of vitamin D resistance in tumors. Splice variants of CYP450 enzymes are common. Existence of CYP24A1 isoforms has been reported recently. We have investigated the presence of CYP24A1 splicing variants (SV) in human colon cancer cell lines and tissue samples. Using a set of primer combination we have screened the entire coding sequence of CYP24A1 and identified three splice variants in colon cancer cell lines. The presence of these SVs in human colon tissue samples showed a correlation with histological type of the tissue and gender of patients. The sequencing of the alternatively spliced fragments showed that two have lost the mitochondrial target domain, while the third lacks the heme-binding domain. All SVs retained their sterol binding domain. Translation of these variants would lead to a dysfunctional enzyme without catalytic activity that still binds its substrates therefore they might compete for substrate with the synthesizing and catabolizing enzymes of vitamin D.
Horváth
H C
HC
1st Department of Medicine, Semmelweis University, Korányi Sándor utca 2/a, 1083 Budapest, Hungary.
Khabir
Z
Z
Nittke
T
T
Gruber
S
S
Speer
G
G
Manhardt
T
T
Bonner
E
E
Kallay
E
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D013250:Steroid Hydroxylases / Q000096:biosynthesis* / Q000235:genetics*; D013261:Sterols / Q000737:chemistry; D065668:Vitamin D3 24-Hydroxylase
D000970:Antineoplastic Agents; D017931:DNA Primers; D013261:Sterols; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase