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Retinoic acid receptor and retinoid X receptor expression in retinoic acid-resistant human tumor cell lines
B M van der Leede1, C E van den Brink, P T van der Saag
1Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht, The Netherlands.
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) RAR alpha, RAR beta, RAR gamma, and the retinoid X receptors (RXRs) RXR alpha, RXR beta, and RXR gamma in the RA-resistant cell lines by northern blotting and by RNase protection analysis for RAR beta. RAR alpha transcripts were constitutively expressed in all cell lines. By contrast, RAR beta 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, RAR gamma 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, RXR alpha was the most abundantly expressed subtype, RXR beta was expressed at low levels, and RXR gamma 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.
Insights
Eleven human tumor cell lines demonstrated resistance to retinoic acid (RA). This resistance was not directly linked to the expression levels of retinoic acid receptors (RARs) or retinoid X receptors (RXRs).
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Retinoic acid (RA) significantly impacts cell proliferation and differentiation.
- Many human cell lines exhibit sensitivity to RA's growth-inhibitory effects.
- Understanding RA resistance in tumor cells is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the retinoic acid (RA) sensitivity of established human solid tumor-derived cell lines.
- To analyze the expression patterns of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in RA-resistant cell lines.
- To determine if RAR or RXR expression correlates with RA resistance in these cell lines.
Main Methods:
- Assessed RA-induced growth inhibition using [3H]thymidine incorporation and cell proliferation assays.
- Examined the expression of RAR alpha, RAR beta, RAR gamma, RXR alpha, RXR beta, and RXR gamma via Northern blotting.
- Utilized RNase protection analysis to specifically quantify RAR beta expression.
Main Results:
- Eleven human cell lines (carcinomas, sarcomas, melanoma) were found to be resistant to RA.
- RAR alpha was constitutively expressed across all tested cell lines.
- RAR beta expression varied, present in seven cell lines and sometimes upregulated by RA; RAR gamma was generally low and unaffected by RA. RXR expression was not modulated by RA in any cell line.
Conclusions:
- The observed RA resistance in human tumor cell lines cannot be solely attributed to the expression levels of RARs or RXRs.
- Further research is needed to elucidate the complex mechanisms underlying retinoic acid resistance in cancer.
- These findings highlight the need for personalized approaches in retinoid-based cancer therapies.