Differential effects of retinoic acid on growth and apoptosis in human colon cancer cell lines associated with the induction of retinoic acid receptor β

Lee, Mi‐Ock; Han, Sun‐Young; Jiang, Shaojun; Park, Jeon Han; Kim, Se Jong

doi:10.1016/s0006-2952(99)00355-x

Cited by 55 publications

(58 citation statements)

References 27 publications

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“…This is in agreement with previous reports, which have shown that RAR-b expression is generally low or absent in pancreatic cancer cells (Kaiser et al, 1997). Although induction of RAR-b has been reported to be an indicator of retinoid response (Seewaldt et al, 1995;Lee et al, 2000;Sun et al, 2000), we could detect no induction of either RAR subtype upon retinoid treatment. This may seem surprising, but is likely to be due to methylation of the RAR-beta gene (Ueki et al, 2000).…”

Section: Experimental Therapeuticssupporting

confidence: 94%

“…A number of earlier studies have established a connection between RAR-g and retinoid induced growth arrest and apoptosis in various cell types. Expression of RAR-b is often lost or decreased in tumour cells (Seewaldt et al, 1995;Wan et al, 1999;Lee et al, 2000;Sun et al, 2000). However, results from a study in melanoma cells showed that, although RAR-b expression was induced by activation of any of the RAR or RXR subtypes, only RAR-g selective compounds were able to induce differentiation followed by apoptosis.…”

Section: Experimental Therapeuticsmentioning

confidence: 99%

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Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-γ and altered expression of Bcl-2/Bax

et al. 2002

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All-trans-retinoic acid and 9-cis-retinoic acid have been reported to have inhibitory effects on pancreatic adenocarcinoma cells and we have shown that this is partly due to induction of apoptosis. In this study, the mechanisms whereby 9-cis-retinoic acid induces apoptosis in these cells were investigated. An involvement of the Bcl-2 family of proteins was shown, such that 9-cisretinoic acid causes a decrease in the Bcl-2/Bax ratio. Overexpression of Bcl-2 also resulted in inhibition of apoptosis induced by 9-cis-retinoic acid. Furthermore, two broad-range caspase inhibitors blocked DNA fragmentation induced by 9-cis-retinoic acid, but had no effect on viability defined by mitochondrial activity. Using synthetic retinoids, which bind selectively to specific retinoic acid receptor subtypes, we further established that activation of retinoic acid receptor-g is essential for induction of apoptosis. Only pan-retinoic acid receptor and retinoic acid receptor-g selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-g is resistant to the effects of 9-cis-retinoic acid. A retinoic acid receptor-b/ g selective antagonist also suppressed the cytotoxic effects of 9-cis-retinoic acid in a dose-dependent manner. This study provides important insight into the mechanisms involved in suppression of pancreatic tumour cell growth by retinoids. Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma.

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Section: Experimental Therapeuticssupporting

confidence: 94%

Section: Experimental Therapeuticsmentioning

confidence: 99%

Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-γ and altered expression of Bcl-2/Bax

et al. 2002

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“…The ability of retinol to inhibit cell growth was examined in three ATRA-resistant human colon cancer cell lines HCT-116 (17), SW620 (18), and WiDR (11). An ATRAsensitive cell line, HCT-15, was chosen to serve as a positive control for the inhibitory effects of ATRA on colon cancer cell growth (19).…”

Section: Resultsmentioning

confidence: 99%

“…There is very little ATRA (4-14 nmol/L) in the serum (21,22). ATRA levels were chosen to match the concentrations of retinol used and to reflect ATRA levels commonly found in the literature (9)(10)(11)23).…”

Section: Resultsmentioning

confidence: 99%

Retinol Inhibits the Growth of All-Trans-Retinoic Acid–Sensitive and All-Trans-Retinoic Acid–Resistant Colon Cancer Cells through a Retinoic Acid Receptor–Independent Mechanism

Park

Dillard²,

Williams³

et al. 2005

Cancer Research

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Retinol (vitamin A) is thought to exert its effects through the actions of its metabolite, all-trans-retinoic acid (ATRA), on gene transcription mediated by retinoic acid receptors (RAR) and retinoic acid response elements (RARE). However, retinoic acid resistance limits the chemotherapeutic potential of ATRA. We examined the ability of retinol to inhibit the growth of ATRA-sensitive (HCT-15) and ATRA-resistant (HCT-116, SW620, and WiDR) human colon cancer cell lines. Retinol inhibited cell growth in a dose-responsive manner. Retinol was not metabolized to ATRA or any bioactive retinoid in two of the cell lines examined. HCT-116 and WiDR cells converted a small amount of retinol to ATRA; however, this amount of ATRA was unable to inhibit cell growth. To show that retinol was not inducing RARE-mediated transcription, each cell line was transfected with pRARE-chloramphenicol acetyltransferase (CAT) and treated with ATRA and retinol. Although treatment with ATRA increased CAT activity 5-fold in ATRAsensitive cells, retinol treatment did not increase CAT activity in any cell line examined. To show that growth inhibition due to retinol was ATRA, RAR, and RARE independent, a pan-RAR antagonist was used to block RAR signaling. Retinol-induced growth inhibition was not alleviated by the RAR antagonist in any cell line, but the antagonist alleviated ATRA-induced growth inhibition of HCT-15 cells. Retinol did not induce apoptosis, differentiation or necrosis, but affected cell cycle progression. Our data show that retinol acts through a novel, RAR-independent mechanism to inhibit colon cancer cell growth. (Cancer Res 2005; 65(21): 9923-33)

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“…In contrast to the reported beneficial clinical effects, there is evidence that intrinsic or acquired resistance can limit retinoid clinical activity. Some colon cancer cell lines, such as HT-29 and HCT-116, are intrinsically resistant to retinoids [5]. Large-scale randomized trials conducted in Europe and the United States showed that moderate doses of natural or synthetic vitamin A compounds were ineffective in reversing premalignancy or in suppressing the recurrence of primary tumors [6,7].…”

Section: Introductionmentioning

confidence: 99%

Celecoxib increases retinoid sensitivity in human colon cancer cell lines

Liu

Zheng

et al. 2010

Cellular and Molecular Biology Letters

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Abstract:Retinoid resistance has limited the clinical application of retinoids as differentiation-inducing and apoptosis-inducing drugs. This study was designed to investigate whether celecoxib, a selective COX-2 inhibitor, has effects on retinoid sensitivity in human colon cancer cell lines, and to determine the possible mechanism of said effects. Cell viability was measured using the MTT assay. Apoptosis was detected via Annexin-V/PI staining and the flow cytometry assay. PGE 2 production was measured with the ELISA assay. The expression of RARβ was assayed via western blotting. The results showed that celecoxib enhanced the inhibitory effect of ATRA in both COX-2 high-expressing HT-29 and COX-2 low-expressing SW480 cell lines. Further study showed the ATRA and celecoxib combination induced greater apoptosis, but that the addition of PGE 2 did not affect the enhanced growth-inhibitory and apoptosis-inducing effects of the combination. Moreover, NS398 (another selective COX-2 inhibitor) did not affect the inhibitory effects of ATRA in the two cell lines. Western blotting showed that the expression of RARβ in HT-29 cell lines was increased by celecoxib, but not by NS398, and that the addition of PGE 2 did not affect the celecoxib-induced expression of the retinoic acid receptor beta. In conclusion, celecoxib increased the expression of RARβ and the level of cellular ATRA sensitivity through COX-2-independent mechanisms. This finding may provide a potential strategy for combination therapy.

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Differential effects of retinoic acid on growth and apoptosis in human colon cancer cell lines associated with the induction of retinoic acid receptor β

Cited by 55 publications

References 27 publications

Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-γ and altered expression of Bcl-2/Bax

Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-γ and altered expression of Bcl-2/Bax

Retinol Inhibits the Growth of All-Trans-Retinoic Acid–Sensitive and All-Trans-Retinoic Acid–Resistant Colon Cancer Cells through a Retinoic Acid Receptor–Independent Mechanism

Celecoxib increases retinoid sensitivity in human colon cancer cell lines

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