Differential effects of retinoic acid on growth and apoptosis in human colon cancer cell lines associated with the induction of retinoic acid receptor beta.
ABSTRACT Retinoids are well known as potential chemopreventive and chemotherapeutic agents against a variety of human cancers. Here, we report that retinoic acid (RA) induced differential growth inhibition in human colon cancer cell lines: while DLD-1, HT-29, and WiDr were relatively resistant, HCT-15 and Colo201 were relatively sensitive. All-trans-retinoic acid caused morphological and biochemical changes such as membrane shrinkage, chromatin condensation, and DNA cleavage, which are typical features of cells undergoing apoptosis in sensitive cell lines. Although retinoic acid receptor (RAR)alpha, beta, gamma and retinoid X receptor alpha were expressed in all cell lines examined, a significant induction of RARbeta by all-trans-RA was observed only in sensitive cell lines, suggesting important roles of RARbeta in RA sensitivity. When a vector containing the RARbeta gene was introduced into a relatively resistant cell line, DLD-1, the cells acquired RA sensitivity. Further, we found that the RARbeta transfectants of DLD-1 expressed an enhanced level of c-Myc and Bax proteins, which may result in the increased susceptibility of the cells to all-trans-RA-induced apoptosis. In summary, our data demonstrated that RA induced growth inhibition and apoptosis in human colon cancer cells and that the induction of RAR3 may mediate the retinoid action.
- SourceAvailable from: Juan Carlos Romero-Benavides[Show abstract] [Hide abstract]
ABSTRACT: Cancer remains a public health problem with a high unmet medical demand. However, in recent decades, the knowledge of several functional molecular and biological traits that distinguish tumor cells from normal cells, known as the hallmarks of cancer as described by Hannahan and Weinberg, has led to new and modern therapeutic approaches against this disease. Most cancer drugs are deliberately developed for specific molecular targets that involve these hallmarks. In this review, we address the currently available cancer drugs and development of new drugs from the perspective of their interaction with these hallmarks as well as the pathways and mechanisms involved.Tumor Biology 01/2014; · 2.84 Impact Factor
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ABSTRACT: Colorectal cancer is ranked among the top leading causes of cancer death in industrialized populations. Polycomb group proteins, including Suz12 and Ezh2, are epigenetic regulatory proteins that act as transcriptional repressors of many differentiation-associated genes and are overexpressed in a large subset of colorectal cancers. Retinoic acid (RA) acts as a negative regulator of PcG actions in stem cells, but has shown limited therapeutic potential in some solid tumors, including colorectal cancer, in part because of retinoic acid receptor β silencing. Through treatment with RA, Suz12 shRNA knockdown, or Ezh2 pharmacological inhibition with 3-deazaneplanocin A (DZNep), we increased TRAIL-mediated apoptosis in human colorectal cancer cell lines. This increased apoptosis in human colon cancer cells after RA or DZNep treatment was associated with a ∼2.5-fold increase in TNFRSF10B (DR5) transcript levels and a 42% reduction in the H3K27me3 epigenetic mark at the TNFRSF10B promoter after DZNep addition. Taken together, our findings indicate that pharmacological inhibition of Polycomb repressive complex 2 histone methyltransferase activity may constitute a new epigenetic therapeutic strategy to overcome RA non-responsiveness in a subset of colorectal tumors by increasing TRAIL-mediated apoptosis sensitivity. J. Cell. Physiol. 228: 764–772, 2013. © 2012 Wiley Periodicals, Inc.Journal of Cellular Physiology 04/2013; 228(4). · 3.87 Impact Factor
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ABSTRACT: Human umbilical cord-derived mesenchymal stem cells (HUCMSCs) are multipotent fetal stem cells that differentiate into various cell lineages. In recent years, they have gained attention for therapeutic applications but very little is known about their sensitivity to chemical agents such as widely used retinoic acid (RA). As a morphogen inducing differentiation of mesenchymal stem cells, RA has for a long time been known to be a potent teratogen promoting craniofacial and limb abnormality in vertebrate embryos. Here, using MTT assay and EB/AO staining as well as TUNEL assay we show that RA in a concentration-dependent manner induces apoptosis through upregulating Caspase expression and increasing Bax/Bcl2 ratio. Moreover, different biological parameters such as initial time seeding, cell density, passage number and duration of RA treatment play a major role in HUCMSCs cytotoxic response to this agent. © 2014 BioFactors, 2014BioFactors 11/2014; · 3.09 Impact Factor