The relationship between renal cell carcinoma and nuclear retinoid/rexinoid receptors

Abstract

Background. Renal cell carcinoma (RCC) is a urologic malignancy with a steady rise in incidence and high mortality rate. Between 60 to 70% of patients with renal cell carcinoma can only be cured with surgery but despite advances in early diagnostis, in around 20-30% of cases there is metastasis. For these patients, chemotherapy and radiotherapy are ineffective and hence the prognosis is poor. Retinoids are biologically active compounds of either natural or synthetic origin that are involved in complex physiological and developmental processes in many tissues including cell proliferation and activation of tumour suppression genes. This article reviews the role of retinoids and their cognate nuclear retinoid/rexinoid receptors in relation to renal cell carcinoma. Methods. A literature search using ScienceDirect and Medline with a focus on the relationship between renal cell carcinoma and nuclear retinoid/rexinoid receptors. Results. Use of retinoids/rexinoids in the treatment of locally advanced and metastatic RCC significantly prolongs median time of tumour progression and overall survival of patients. Combination therapy with other preparations has greater efficacy than treatment with retinoids alone. Patient survival can be predicted on the basis of the expression of different all-trans retinoic acid receptor (RAR) and 9-cis retinoic acid receptor (RXR) subtypes. Conclusions. Since nuclear retinoid receptors play a crucial role as ligand-activated, DNA binding, trans-acting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes, retinoids might be an alternative approach for the treatment of renal cell carcinoma.

Retinoic acid receptors: From molecular mechanisms to cancer therapy

“…About two thirds of patients with RCC can be treated with surgery and their prognosis is excellent. However, for patients with an advanced/metastatic RCC (about 20-30%), the prognosis is poor and chemotherapy and radiotherapy treatments yield relative weak or ineffective results (Escudier et al, 2013;Lenko et al, 2013). For many years, cytokine-based therapy, comprising IFN-α and/or IL-2, has been the standard treatment of advanced/metastatic RCC, with modest clinical benefit and significant toxicity.…”

“…Based on evidence suggesting that all-trans-RA modulates IFN-inducible gene expression by augmenting the transcription of IFN-stimulated genes (Giandomenico et al, 1997), several phase II trials tested the ability of 13-cis-RA to increase IFN-α-2A response in advanced/metatstatic RCC. The combined treatment with 13-cis-RA and IFN-α-2A induces a significant improvement in both progression free and overall survival for patients with advanced/metastatic RCC when compared with IFN-α-2A or 13-cis-RA used as single agents (Aass et al, 2005;Berg et al, 1997Berg et al, , 1999Lenko et al, 2013;Motzer et al, 1999Motzer et al, , 2000.…”

“…Interestingly, RCC clinical responses may be predicted on the basis of the expression of different RAR and RXR subtypes (Berg et al, 1999;Boorjian et al, 2007;Lenko et al, 2013;Motzer et al, 1999Motzer et al, , 2000. Up-regulation of RARβ mRNA expression in RCC cells significantly correlates with major response to IFN-α-2A or 13-cis-RA treatment, thus supporting an antitumor effect of RARβ in RCC (Berg et al, 1999).…”

Bexarotene – a novel modulator of AURKA and the primary cilium in VHL-deficient cells

“…The efficacy of retinoids in metastatic RCC was evaluated in the early 1990s with combination therapy reported to be more promising than mono-therapy for treatment of RCC (Aass et al, 2005; Berg et al, 1999; Boorjian et al, 2007; Motzer et al, 1999, 2000). Detailed evaluations revealed that all types of RAR (α, β and γ) and RXR (α and β) subtypes of receptors are expressed in RCC, although RXRγ was lost in advanced stage RCC (Lenko et al, 2013).…”