Retinoic acid receptor and retinoid X receptor expression in retinoic acid—resistant human tumor cell lines

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Abstract
Retinoic acid (RA) has profound effects on cell proliferation and differentiation both in vitro and in vivo. Many human cell lines are known to be sensitive to the growth‐inhibitory action of RA. We analyzed established human solid tumor—derived cell lines for their RA sensitivity. Growth inhibition by RA in monolayer was examined by [3H]thymidine incorporation and cell proliferation. Here we report that 11 widely used human cell lines were RA resistant. The majority are carcinoma derived (A‐431, BT‐20, C‐41, ACHN, HCT116, 293, A549, and PA‐1); two are sarcoma derived (Saos‐2 and A673); and one is a melanoma cell line (A‐375). Since nuclear retinoid receptors are implicated in the biological effects of RA, we examined the expression of retinoic acid receptors (RARs) RARα, RARβ, RARγ, and the retinoid X receptors (RXRs) RXRα, RXRβ, and RXRγ in the RA‐resistant cell lines by northern blotting and by RNase protection analysis for RARβ. RARα transcripts were constitutively expressed in all cell lines. By contrast, RARβ was expressed in only seven RA‐resistant cell lines (Saos‐2, ACHN, 293, A549, A‐375, A673, and PA‐1), and its level was enhanced by RA in some cases. In most cell lines, RARγ expression was low and was not affected by RA. The RXR genes showed a very distinct expression pattern in the group of selected cell lines. In general, RXRα was the most abundantly expressed subtype, RXRβ was expressed at low levels, and RXRγ could not be detected. In none of the RA‐resistant cell lines was RXR expression modulated by RA. The results presented here indicate that the resistance of these human tumor cell lines to RA cannot be simply correlated with expression of RAR or RXR or both.