Enhanced turnover of all-trans-retinoic acid and increased formation of polar metabolites in head and neck squamous cell carcinoma lines compared with normal oral keratinocytes
I. Klaassen et al., Enhanced turnover of all-trans-retinoic acid and increased formation of polar metabolites in head and neck squamous cell carcinoma lines compared with normal oral keratinocytes, CLIN CANC R, 7(4), 2001, pp. 1017-1025
Retinoids show promise in the treatment of various (pre)malignancies, inclu
ding head and neck squamous cell carcinoma (HNSCC). Previous studies have s
hown that the metabolic pathways of retinoids are important in the anticanc
er effect of retinoids, and that these pathways may change during carcinoge
nesis. In the present study, we analyzed HNSCC cell lines (n = 11) and norm
al oral keratinocyte cultures (It = II) by reverse-phase high-performance l
iquid chromatography and conducted growth inhibition assays, We demonstrate
here that in contrast to normal oral keratinocytes, HNSCC cell lines: (a)
had averaged a 17-fold greater turnover rate of all-trans-retinoic acid (RA
); (b) had a 19-fold less RA-induced growth inhibition; (c) were able to fo
rm polar metabolites; and (d) were able to catabolize 4-oxo-RA. Furthermore
, the mRNA expression of the RA-specific 4-hydroxylase, CYP26A1, was dramat
ically increased after RA-induction in the two HNSCC cell lines with the hi
ghest metabolism, was undetectable in normal keratinocytes, and was not ind
ucible by RA, Next, introduction of CYP26A1 cDNA in a low-metabolizing HNSC
C cell line resulted in an Ii-fold higher turnover rate of RA and a 12-fold
increase in the amount of polar metabolites, but it did not change sensiti
vity to RA, These observations point to fundamental changes in RA metabolis
m pathways during HNSCC carcinogenesis and may provide clues to a more rati
onal approach for RA-mediated intervention.