**2.5 ADHs (alcohol dehydrogenases)**

ADHs are a family of alcohol dehydrogenases involved in retinoid metabolism via conversion of retinol to retinaldehyde by catalyzing the NAD-dependent oxidation of all-trans-retinol and its derivatives such as all-trans-4-hydroxyretinol. These enzymes metabolize a wide variety of substrates, including ethanol, retinol,

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**Figure 1.**

segment as a gene cluster.

**2.6 RBPs (retinol-binding proteins)**

aliphatic alcohols, hydroxysteroids, and products of lipid peroxidation. ADHs consist of several homo- and heterodimers of alpha, beta, and gamma subunits, which plays major roles in ethanol catabolism. For example, three genes encoding alpha, beta, and gamma subunits of ADH1 are tandemly organized in a genomic

*enzymes. STRA6 = stimulated by retinoic acid 6, RDHs = retinol dehydrogenases, ADHs = alcohol dehydrogenases, RBPs = retinol binding proteins, ALDHs = aldehyde dehydrogenases, CRABPs = cellular retinoic acid binding proteins, CYP26A1 = cytochrome p450 family 26 subfamily a member 1, RARE = retinoic* 

*acid response element; RXRs = retinoid X receptors, RARs = retinoic acid receptors.*

*This figure illustrates a simplified schematic of the RA signaling pathway, which plays a key role in embryogenesis and adult tissue homeostasis. The cell surface protein STRA6 accepts all-trans retinol from the extracellular milieu to transfer it across the cell membrane into the cytoplasm. STRA6 does not transport retinoic acid. After transfer or diffusion into cytoplasm, the internalized free retinol is bound to CRBP or is oxidized to retinal by retinol dehydrogenases (RDH) or alcohol dehydrogenases (ADH) and eventually to form all-trans retinoic acid (ATRA) by aldehyde dehydrogenases (ALDHs). ATRA then binds to cellular retinoic acid-binding proteins (CRABPs), which transfers ATRA to the nucleus. Once localized in the nucleus, ATRA serves as a ligand for binding to retinoid X receptors (RXRs) and retinoic acid receptors (RARs). Once ATRA travels to the nucleus, it binds RARs to induce the transcription of retinoid-responsive genes. Specifically, bound ATRA (or other ligands such as 9-cis) induces formation of a heterodimer (RA:RAR:RXR) in a complex at retinoic acid receptor elements on DNA, which then is able to induce transcription of RA-response genes. Thus, the RAR:RXR heterodimer acts as the main transcription factor in the classical RA signaling pathway. Nonetheless, the rate of formation of the RA:RAR:RXR complex, is still affected by other intracellular RA binding proteins such as CRABPs, which can sequester RA in the cytosol and limit the amount of RA available for binding to RARs. CRABPs can also facilitate RA degradation by directing RA to CYP26A1 RA-degrading* 

RBP1 (Retinol Binding Protein 1) and RBP2 (Retinol Binding Protein 2) are cytoplasmic retinol-binding proteins, which contribute to retinol uptake, storage,

*Retinoids in Treatment of Colorectal Cancer DOI: http://dx.doi.org/10.5772/intechopen.93699* *Retinoids in Treatment of Colorectal Cancer DOI: http://dx.doi.org/10.5772/intechopen.93699*

### **Figure 1.**

*Colorectal Cancer*

would otherwise be facing a highly fatal illness. The precise mechanism involved in triggering APL cells have been extensively studied with the hope of understanding how it can be applied to trigger differentiation in other cancer types. What appears to be the basis for clinical success in treating APL is that the RA/arsenic combination not only induces terminal differentiation, but it also abrogates self-renewal of APL SCs [12]. Thus, future retinoid-based treatments for other cancers will likely necessitate drug combinations that incorporate a RA signaling differentiation therapy and a SC-targeting therapy that inhibits cancer SC self-renewal.

To understand how the RA signaling pathway is altered in cancer and to provide a basis for designing retinoid-based treatment approaches to cancer, we provide a brief description of the key components in the RA signaling pathway. The reader is referred to Das et al. [13] for more detailed information. Listed below are the main proteins essential to proper functioning of the RA signaling pathway. A simplified schematic

STRA6 is a cell surface protein that functions as a receptor to accept all-trans retinol from the extracellular retinol-binding protein RBP4 and to transport retinol across the cell membrane. STRA6 removes the retinol from RBP4 and transfers it to

LRAT is an enzyme that converts retinol to all-trans retinyl esters, which is a storage form of vitamin A. LRAT also functions to enhance cellular uptake of retinol by STRA6, which contributes to the activation of the RA signaling cascade.

RDHs are a family of dehydrogenase enzymes involved in the conversion of retinol to retinaldehyde by catalyzing the oxidation of cis-isomers of retinol, including 11-cis-, 9-cis-, and 13-cis-retinol in an NAD-dependent manner. This family of short-chain dehydrogenases/reductases functions to catalyze the final

DHRS3 is an oxidoreductase that catalyzes the oxidation/reduction of alltrans-retinal to all-trans-retinol in the presence of NADPH. DHRS3 is essential for

ADHs are a family of alcohol dehydrogenases involved in retinoid metabolism

via conversion of retinol to retinaldehyde by catalyzing the NAD-dependent oxidation of all-trans-retinol and its derivatives such as all-trans-4-hydroxyretinol. These enzymes metabolize a wide variety of substrates, including ethanol, retinol,

preventing the formation of excess RA during embryonic development.

**2. Key components of the retinoic acid signaling pathway**

of the RA signaling pathway is illustrated in **Figure 1**.

RBP1 in the cytoplasm. STRA6 does not transport RA.

**2.1 STRA6 (stimulated by retinoic acid 6)**

**2.2 LRAT (lecithin retinol acyltransferase)**

step in the biosynthesis of 11-cis retinaldehyde.

**2.4 DHRS3 (retinaldehyde reductase-3)**

**2.5 ADHs (alcohol dehydrogenases)**

**2.3 RDHs (retinol dehydrogenases)**

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*This figure illustrates a simplified schematic of the RA signaling pathway, which plays a key role in embryogenesis and adult tissue homeostasis. The cell surface protein STRA6 accepts all-trans retinol from the extracellular milieu to transfer it across the cell membrane into the cytoplasm. STRA6 does not transport retinoic acid. After transfer or diffusion into cytoplasm, the internalized free retinol is bound to CRBP or is oxidized to retinal by retinol dehydrogenases (RDH) or alcohol dehydrogenases (ADH) and eventually to form all-trans retinoic acid (ATRA) by aldehyde dehydrogenases (ALDHs). ATRA then binds to cellular retinoic acid-binding proteins (CRABPs), which transfers ATRA to the nucleus. Once localized in the nucleus, ATRA serves as a ligand for binding to retinoid X receptors (RXRs) and retinoic acid receptors (RARs). Once ATRA travels to the nucleus, it binds RARs to induce the transcription of retinoid-responsive genes. Specifically, bound ATRA (or other ligands such as 9-cis) induces formation of a heterodimer (RA:RAR:RXR) in a complex at retinoic acid receptor elements on DNA, which then is able to induce transcription of RA-response genes. Thus, the RAR:RXR heterodimer acts as the main transcription factor in the classical RA signaling pathway. Nonetheless, the rate of formation of the RA:RAR:RXR complex, is still affected by other intracellular RA binding proteins such as CRABPs, which can sequester RA in the cytosol and limit the amount of RA available for binding to RARs. CRABPs can also facilitate RA degradation by directing RA to CYP26A1 RA-degrading enzymes. STRA6 = stimulated by retinoic acid 6, RDHs = retinol dehydrogenases, ADHs = alcohol dehydrogenases, RBPs = retinol binding proteins, ALDHs = aldehyde dehydrogenases, CRABPs = cellular retinoic acid binding proteins, CYP26A1 = cytochrome p450 family 26 subfamily a member 1, RARE = retinoic acid response element; RXRs = retinoid X receptors, RARs = retinoic acid receptors.*

aliphatic alcohols, hydroxysteroids, and products of lipid peroxidation. ADHs consist of several homo- and heterodimers of alpha, beta, and gamma subunits, which plays major roles in ethanol catabolism. For example, three genes encoding alpha, beta, and gamma subunits of ADH1 are tandemly organized in a genomic segment as a gene cluster.

### **2.6 RBPs (retinol-binding proteins)**

RBP1 (Retinol Binding Protein 1) and RBP2 (Retinol Binding Protein 2) are cytoplasmic retinol-binding proteins, which contribute to retinol uptake, storage, and retinoid homeostasis. Specifically, RBP1 is the carrier protein for transport of retinol from the liver storage site to peripheral tissue. RBP2 also plays an important role in the uptake and intracellular transport of retinol, which is necessary for intracellular metabolism of vitamin A.
