Abstract
Retinoid compounds induce multiple molecular effects that need to be taken into consideration in the development of theses agents as pharmaceuticals for cancer chemoprevention. Inhibition of cancer cell growth by retinoids is thought to occur through at least two mechanisms of transcriptional regulation resulting from direct binding of retinoids to nuclear retinoid receptors (RARs and RXR’s). First, the nuclear receptors induce or repress expression of specific genes by direct binding to retinoic acid response elements (RAREs) in gene promoters. Second, the nuclear receptors antagonize transactivation of activator protein-1 (AP-1) promoter elements by the AP-1 transcription factors. The objective of this study was to determine the contributions of RARE transactivation and AP-1 antagonism to the mechanism of growth inhibition in cervical cancer cell lines by: the 9-cis isomer of retinoic acid (9-cis-RA), which binds both RARs and RXRs; and a series of synthetic retinoids, called heteraoarotinoids, that possess various receptor specificities and reduced toxicity. The effects of these compounds on reporter gene expression and proliferation were measured in CC-1 and SiHa cell lines stably transfected with RARE or AP-1 reporter plasmids or a retrovirus harboring an inducibile AP-1 protein that is a dominant negative mutant of c-Jun (TAM67). In the CC-1 cell line, which exhibited high AP-1 activity, retinoid growth inhibition significantly correlated with both RARE transactivation and AP-1 repression, was antagonized by superinduction of AP-1 with TPA (12-O-tetradecanoylphorbol-13-acetate) and was enhanced by TAM67. In the SiHa cell line, which exhibited low AP-1 activity, RARE transactivation also significantly correlated with growth inhibition, but AP-1 induction, in contrast to AP-1 repression, correlated with growth inhibition. Furthermore, TPA superinduction of AP-1 did not attenuate retinoid growth inhibition activity in SiHa. In conclusion, repression of AP-1 with retinoids may only be effective against a subset of tumors with high AP-1 activity.
Highlights
Retinoic acid (RA) and synthetic analogs, called retinoids, are promising anti-cancer agents based on their abilities to regulate growth, differentiation, apoptosis, angiogenesis and the immune system[1]
Correlation of retinoic acid response elements (RAREs) and activator protein-1 (AP-1) transactivation with growth inhibition: Transactivation of RARE and AP-1 DNA elements by transcription factors endogenous to cancer cells was measured in CC-1 and SiHa cell lines that were stably transfected with reporter plasmids
These plasmids encode the chloramphenicol acetyl transferase (CAT) gene under the control of an RARE or an AP-1 DNA binding sites, so that the levels of CAT produced in the cells represent a measure of transcriptional regulation from the RARE or AP-1 DNA binding sites
Summary
Retinoic acid (RA) and synthetic analogs, called retinoids, are promising anti-cancer agents based on their abilities to regulate growth, differentiation, apoptosis, angiogenesis and the immune system[1] These activities are mediated by two classes of nuclear retinoid receptors (RARs and RXRs), which act as transcription factors by binding to retinoic acid response elements (RAREs) as dimers[2,3]. Incorporation of a heteroatom into the cyclic ring of arotinoids resulting in compounds called heteroarotinoids reduced the toxicity 1000fold in the diaryl TTNPB structure and 3000 fold in the monoaryl heteroarotinoid structure[11]. This class of compounds has the potential for clinical application as anticancer drugs. The Chemoprevention Working Group to the American Association for Cancer Research concluded that retinoids are considered one of the most promising classes of cancer chemoprevention agents[12]
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