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

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.