Effect of 13-cis-retinoic acid on tumor prevention, tumor growth, and metastasis in experimental colon cancer

doi:10.1016/0022-4804(87)90130-2

Journal of Surgical Research

Volume 43, Issue 6, December 1987, Pages 550-557

https://doi.org/10.1016/0022-4804(87)90130-2 Get rights and content

Abstract

The effect of 13-cis-retinoic acid (13-cis-RA) on 1,2-dimethylhydrazine (DMH)-induced colon cancer in male, random bred, Sprague-Dawley (S-D) and inbred Wister/Furth (W/Fu) rats and on isograft tumor growth and metastases in a Brown Norwegian (BN) × W/Fu F₁ rat was studied. 13-cis-RA (300 mg/kg diet) was administered to S-D rats 1 week before commencing DMH injections and for the duration of the experiment. W/Fu rats received 13-cis-RA (10 mg/kg weight × 5 days) 6 weeks after DMH injection had begun and monthly thereafter. Primary tumors were detected by serial laparotomy under ether anesthesia in both strains. The time to tumor onset was significantly delayed in treated groups, S-D and W/Fu, P = 0.0339 and 0.0322, respectively (Mantel-Haenszel test), compared with placebo-treated controls. 13-cis-RA (15 mg/kg weight) administered 2 days before and for the duration of isograft tumor growth (DMH 2054, a well-differentiated mucin-producing colon adenocarcinoma that spontaneously metastasized to lung) had no effect on tumor growth or metastasis in the BN × W/Fu F₁ rat. The findings suggest that the role of 13-cis-RA is in colon cancer prevention and not in its treatment either in an adjuvant or established setting.

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The primary assertion of this study is that AMPK mediates some of the metabolic and cytoskeletal effects of retinoic acid. The role of retinoic acid has previously been evaluated in conjunction with differentiation (1) and anti-tumor functions (2–5). The cytoskeleton-altering properties of retinoic acid appear to be responsible for its role in differentiation, and may also contribute to its observed anti-tumor effects.
Retinoic acid (RA) is one of the major components of vitamin A. In the present study, we found that retinoic acid activated AMP-activated protein kinase (AMPK). RA induced Rac1-GTP formation and phosphorylation of its downstream target, p21-activated kinase (PAK), whereas the inhibition of AMPK blocked RA-induced Rac1 activation. Moreover, cofilin, an actin polymerization regulator, was activated when incubated with RA. We then showed that inhibition of AMPK by compound C, a selective inhibitor of AMPK, or small interfering RNA of AMPK α1 blocked RA-induced cofilin phosphorylation. Additionally, we found that retinoic acid-stimulated glucose uptake in differentiated C2C12 myoblast cells and activated p38 mitogen-activated protein kinase (MAPK). Finally, the inhibition of AMPK and p38 MAPK blocked retinoic acid-induced glucose uptake. In summary, our results suggest that retinoic acid may have cytoskeletal roles in skeletal muscle cells via stimulation of the AMPK-Rac1-PAK-cofillin pathway and may also have beneficial roles in glucose metabolism via stimulation of the AMPK-p38 MAPK pathway.
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Mutations in adenomatous polyposis coli (APC) underlie the earliest stages of colorectal carcinogenesis. Consequences of APC mutation include stabilization of β-catenin, dysregulation of cyclooxygenase-2 (COX-2) expression, and loss of retinoic acid production, events with poorly defined interactions. Here we showed that treatment of zebrafish expressing a truncated form of Apc with either retinoic acid or a selective COX-2 inhibitor decreased β-catenin protein levels and downstream signaling events. Interestingly, the destruction of β-catenin in apc mutant embryos following Cox-2 inhibition required the presence of truncated Apc. These findings support roles for retinoic acid and Cox-2 in regulating the stability of β-catenin following Apc loss. Furthermore, truncated Apc appears to retain the ability to target β-catenin for destruction, but only in the absence of Cox-2 activity. This novel function of truncated Apc may provide a molecular basis for the efficacy of COX-2 inhibitors in the treatment of colon cancer.
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Recent studies have shown that retinoids and vitamin E are effective growth inhibitors of numerous cancer cell lines. In the present study, vitamin A derivative 13-cis-retinoic acid and α-tocopherol succinate were administered to HT-29 human colon adenocarcinoma cells individually or in combination for a period of 8 days. Cells treated with individual compounds for 8 days attained 80% of the control population. Cells treated with both compounds reached 25% of the control population after 4 days and less than 1% of the control population after 8 days. After 4 days, treated cells became cytostatic, with more than 50% of the cells detaching by day 8. This synergistic effect was specific only for HT-29 cells as compared with normal human colon cells. Treatment resulted in morphological and biochemical changes indicative of apoptotic cell death, including cell cycle blockage at the G₁/S interphase, chromatin condensation, nuclear fragmentation, DNA damage, and caspase 3 activation.
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Differential Response of β-Catenin/TCF and Retinoic Acid-responsive Promoters to Retinoic Acid in Colon Cancer Cells—In earlier studies we showed that β-catenin/TCF signaling activity could be inhibited by RA in Caco2 and HT29 colon cancer cells and in β-catenin-transfected SKBR3 and MCF-7 breast cancer cells (3). All these cell lines respond to retinoic acid by decreased proliferation and increased activation of retinoic acid-sensitive genes and RARE reporters (14, 15). However, not all colon cancer cells respond to retinoic acid by decreasing growth even though RA-treatment continues to activate RARE reporters in these cells (2).
The signaling/oncogenic activity of β-catenin can be repressed by the activation of nuclear receptors such as the vitamin A, vitamin D, and androgen receptors. Although these receptors directly interact with β-catenin and can sequester it away from its transcription factor partner T-cell factor, it is not known if this is the mechanism of trans-repression. Using several different promoter constructs and nuclear receptors and mammalian two-hybrid and mutation analyses we now show that interaction with the co-activator, p300, underlies the trans-repression of β-catenin signaling by nuclear receptors and their ligands.
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There is also increasing evidence that retinoids down-regulate the telomerase in a pathway distinct from cell differentiation, implicating the role of retinoids in replicative senescence (45, 46). Complementaryin vivo studies have demonstrated the ability of retinoids to inhibit tumor formation in carcinogenesis models, typically at the step of tumor promotion (47, 48). Importantly, these studies have led to clinical trials of retinoids in chemoprevention of a number of epithelial and non-epithelial cancers (49).
The expression of human papillomavirus (HPV) E6 oncoprotein is causally linked to high-risk HPV-associated human cancers. We have recently isolated hADA3, the human homologue of yeast transcriptional co-activator yADA3, as a novel E6 target. Human ADA3 binds to the high-risk (cancer-associated) but not the low-risk HPV E6 proteins and to immortalization-competent but not to immortalization-defective HPV16 E6 mutants, suggesting a role for the perturbation of hADA3 function in E6-mediated oncogenesis. We demonstrate here that hADA3 directly binds to the retinoic X receptor (RXR)α in vitro and in vivo. Using chromatin immunoprecipitation, we show that hADA3 is part of activator complexes bound to the native RXR response elements within the promoter of the cyclin-dependent kinase inhibitor gene p21. We show that hADA3 enhances the RXRα-mediated sequence-specific transactivation of retinoid target genes, cellular retinoic acid-binding protein II and p21. Significantly, we demonstrate that E6 inhibits the RXRα-mediated transactivation of target genes, implying that perturbation of RXR-mediated transactivation by E6 could contribute to HPV oncogenesis.

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Effect of 13-cis-retinoic acid on tumor prevention, tumor growth, and metastasis in experimental colon cancer

Abstract

Amer. J. Clin. Nutr.

Amer. J. Clin. Nutr.

Lancet

Lancet

J. Urol.

Blood

Nutritional Blindness: Xerophthalmia and Keratomalacia

Tissue changes following deprivation of fat-soluble A vitamin

J. Exp. Med.

The changes in the para-ocular glands which follow the administration of diets low in fat soluble A, with notes of the effects of these same diets on the salivary glands and the mucosa of the larynx and trachae

Johns Hopkins Hosp. Bull.

Serum Vitamin A (retinol) and cancer incidence in Evans County, Georgia

J. Natl. Cancer Inst.

Relation of serum vitamins A and E and carotenoids to the risk of cancer

N. Engl. J. Med.

Serum retinol and risk of subsequent cancer: Extension of the Evans County, Georgia Study

J. Natl. Cancer Inst.

Inhibition of rat mammary carcinogenesis by short dietary exposure to retinyl acetate

Cancer Res.

Inhibition of benzo[a]pyrene induced mammary carcinogenesis by retinyl acetate

J. Natl. Cancer Inst.

13-cis-Retinoic acid: Inhibition of bladder carcinogenesis in the rat

Science

Influence of delayed administration of retinyl acetate on mammary carcinogenesis

Cancer Res.

Effect of delay in administration of 13-cis-retinoic acid on the inhibition of urinary bladder carcinogenesis in the rat

Cancer Res.

Inhibition of growth and progression of a transplantable rat chondrosarcoma by three retinoids

Cancer Treat. Rep.

Antitumor action of vitamin A in mice inoculated with adenocarcinoma cells

J. Natl. Cancer Inst.

Inhibition of the growth and development of a transplantable murine melanoma by vitamin A

Science