Abstract
Anaplastic thyroid cancer (ATC) is a highly lethal undifferentiated malignancy without reliable therapies. Retinoic acid (RA) has been employed to promote redifferentiation of thyroid cancers by increasing their I131 uptake and radio-sensitivity, but its effect(s) on ATCs has not yet been ascertained. Likewise, resveratrol induces cancer redifferentiation but, also in this case, its effects on ATCs remain unknown. These issues have been addresses in the current study using three human ATC cell lines (THJ-11T, THJ-16T, and THJ-21T) through multiple experimental approaches. The results reveal that RA exerts a small inhibitory effect on these cell lines. In comparison with normally cultured cells, the total cell number in resveratrol-treated THJ-16T and THJ-21T cultures significantly decreased (p < 0.05), and this effect was accompanied by reduced Cyclin D1 immuno-labeling, increased apoptotic fractions, and distinct caspase-3 activation. Resveratrol failed to inhibit growth but enhanced RA sensitivity of THJ-11T cells, suppressed peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ), and upregulated cellular retinoic acid-binding protein 2 (CRABP2) and retinoic acid receptor beta (RAR-β) expression. Increased thyroglobulin (Tg) and E-cadherin levels and appearance of membranous E-cadherin were evidenced in resveratrol-treated THJ-11T cells. Our results demonstrate for the first time: (1) the therapeutic value of resveratrol by itself or in combination with RA in the management of ATCs, (2) the capacity of resveratrol to overcome RA resistance in ATC cells by reprogramming CRABP2/RAR- and fatty acid-binding protein 5 (FABP5)/PPAR-β/δ-mediated RA signaling, and (3) the redifferentiating potential of resveratrol in ATC cells.
Highlights
Thyroid cancer (TC) is the commonest endocrine malignancy and its incidence shows a steady increase in most countries [1]
The results of hematoxylin-eosin (H/E) morphological staining and immunocytochemical staining demonstrate that after 10 μM Retinoic acid (RA) treatment for 48 h, no distinct cell death is observed in THJ-11T, THJ-16T, and THJ-21T cell populations (Figure 1A) and the levels and intracellular distribution patterns of Cyclin D1 remain unchanged (Insets of Figure 1A). 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) cell proliferation assays (Figure 1B) reveal that after 5 μM and 10 μM RA treatment for 48 h, the optical density (OD) values of THJ-11T, THJ-16T, and THJ-21T cells are not significantly altered (p > 0.05) compared with that of the 0.2% dimethyl sulfoxide (DMSO)-treated counterparts (Control)
The results clearly demonstrate that the ratio of cellular retinoic acid-binding protein 2 (CRABP2)/fatty acid-binding protein 5 (FABP5) is imbalanced THJ-11T cells because of an extremely low CRABP2 expression; this situation is reversed upon resveratrol treatment with a remarkably increased level of CRABP2 and largely unchanged FABP5 expression
Summary
Thyroid cancer (TC) is the commonest endocrine malignancy and its incidence shows a steady increase in most countries [1]. According to the criteria of the World Health Organization (WHO), thyroid cancers are classified into five histological subtypes, including follicular carcinoma, papillary carcinoma, medullary carcinoma, undifferentiated anaplastic thyroid carcinoma (ATC), and others [3]. The majority of thyroid cancers are diagnosed as papillary carcinomas with promising prognosis [4], while ATC, though having a low incidence (1.7% among all thyroid cancer cases), accounts for 33–50% of TC-related death because of its aggressive growth, distal metastases formation and, especially, the lack of reliable adjuvant treatments [5]. Promising results were obtained in RA-treated ATC cells (FRO) [9], the clinical efficacy of RA-based redifferentiation therapy is still in dispute [10,11]. It is necessary to explore alternative adjuvant agents for a better treatment of ATCs
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