Abstract
The nuclear retinoic acid receptor may play a critical role in the process of lung carcinogenesis. Alteration or loss of nuclear retinoic acid receptors (RARs) has been associated with progression in premalignant and malignant tissues and it is associated with malignant transformation in human cells. Vitamin A derivates, such as retinoic acid, have emerged as adjuvant to therapy in several types of cancer with favorable effects. Retinoic acid regulates the expression of target genes through the binding and activation of RARs, inhibiting growth proliferation. Diverse studies have evaluated different retinoids alone or in combination with chemotherapy in lung cancer, from which results have been controversial with benefits observed only in the subpopulation with high levels of triglycerides. Additionally, several large randomized trials using retinoids to prevent tobacco-related cancer have failed; due to the latter the use of retinoids in clinical trials remains controversial. However they could reduce the risk of cancer development in non-smokers. There is evidence that retinoids have different effects on lung cancer; still the identification of biomarkers could determinate their benefits as preventive or therapy agents. This review describes the RAR alterations during the development of Non-Small Cell Lung Cancer and sets out the importance of several cancer treatments with retinoid compounds.
Highlights
The retinoids are a wide group of compounds, derived from Vitamin A, which are required for maintaining many essential physiological processes, such as: embryonic development, cell growth, differentiation and apoptosis [1] [2]
While retinoic acid receptors (RARs) can be activated by all-trans retinoic acid (ATRA) and 9-cis-Retinoic acid (RA), Retinoid X Receptors (RXRs) are exclusively activated by 13-cis-RA and bexarotene; ATRA can presumably activate RXRs through its isomerization to 9-cis-RA, which is known to occur in living cells [12] [13]
Multiple studies have demonstrated that this phenomenon contributes to the loss of the RARs and RXRs expression leading to the development of non-small cell lung cancer (NSCLC) [36]
Summary
The functions of RA signaling are mediated by two different classes of receptors, the Retinoic Acid Receptors RARs) and the Retinoid X Receptors (RXRs), each class with three different subtypes (α, β and γ). The heterodimers bind to specific response elements (e.g. RAREs and RXREs) in genes promoter regions via their specific DNA-binding domains [12]. The RXRs work as a transcription factor, binding to specific six-base-pair sequences of DNA in the promoter regions of genes. The C region has a highly conserved sequence of 66 amino acids that contains two zinc fingers which correspond to a DNA binding domain (Figure 1, DNA-BD) responsible for specific response element recognition. Regarding the RXRs, their sequence is divided into several regions, which possess the same inter-type domain conservation as RARs [16] [17]. The differences between the response profiles for each of the RARs have been used to evaluate their participation in multiple cellular processes, with an attempt to correlate with new the rapeutic applications
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