Our society has a fixation with the youth. Everywhere we look, there are emerging new products to overcome the aging process. Interestingly enough, a vast majority of these products employ the use of retinoid compounds, and a deeper understanding of retinoid metabolism in cancer cells could potentially yield a new target for anticancer drugs.
The retinoid class of chemical compounds is composed of retinols, retinals, and retinoic acids (Mukherjee et al., 2006). Derived from vitamin A, they share a chemical backbone consisting of 20 carbon atoms, a cyclohexene ring, a polyene side chain, and a polar end group that can be modified to form various derivatives (Figure 1;(Ross et al., 2003)
Figure 1: Retinoid Compounds include Retinals, Retinols, and Retinoic Acids (Ross et al. 2003)
Retinols are oxidized by alcohol dehydrogenases to retinals, which are oxidized once more to produce the retinoic acids that are used in skincare products. In the cell, retinoic acids have two roles; the inhibition of collagen degradation and the activation of retinoic acid receptors (RARs) to induce proliferation (Mukherjee et al. 2006).
Under normal conditions, retinoid metabolism is tightly regulated at both ends. Without retinoic acid bound, RARs form a complex with Retinoic X Receptors (RSX) that binds to the promoter region of proliferative genes to prevent transcription. Additionally, the relative concentrations of the precursors for retinoic acid, retinol and retinal, are maintained by the enzyme Aldo Keto Reductase 1B10 (AKR1B10). This enzyme reduces excess retinals back to retinols to prevent the accumulation of retinoic acids (Figure 2)(Matsunaga et al. 2013).
Figure 2: Retinoid Metabolism: (1,2) The accumulation of Reactive Oxidative Species (ROS) induces the transcription of AKR1B10 (3,4) AKR1B10 reduces retinals back to retinols (5) The accumulation of retinoic acid activates Retinoic Acid Receptors (RAR) for proliferation(Ruiz & Porté 2012)
When the cell is exposed to reactive oxidative species (ROS), whether from UV radiation, smoking, or exposure to carcinogens, the transcription of genes for the AKR1B10 enzyme is activated (Hyndman et al. 2005). This is accomplished by the Nrf2 transcription factor, which is typically inactive under regular conditions (Barski et al. 2009). When ROS accumulate within the cytosol, Nrf2 is activated and induces the transcription of AKR1B10 (Kansanen et al. 2013). The overexpression of AKR1B10 from ROS contributes to carcinogenesis through uncontrolled cell proliferation, a hallmark of cancer. As the excess AKR1B10 enzymes continue to push retinoid metabolism in the reverse direction by reducing retinals back to retinols, the retinoic acid levels begin to decline. In return, the cell attempts to compensate for the loss of retinoic acid and induces retinoid metabolism, constantly producing retinoic acids that will increase proliferation (Ruiz & Porté 2012). This loop of hyperactivity also facilitates chemoresistance, as the ROS generated by chemotherapeutic drugs can illicit this response, allowing cancer cells to survive and spread(Matsunaga et al. 2013).
While the mechanisms behind the regulation of retinoid metabolism remain complex and under active research, AKR1B10 poses as a potential target for future anticancer drugs as its overexpression has been found in lung, colon, and breast cancers, and especially in tumors that have become chemoresistant (Matsunaga et al. 2013). The application of skincare products that contain retinoic acid could prove to have preventative effects on carcinogenesis, as the presence of retinoic acid may limit the cell’s ability to hyperactivate retinoid metabolism. This effect has been indicated in animal studies, but future studies with humans will have to conclude this (Das et al., 2013).
WORKS CITED
Barski, O.A., Tipparaju, S.M. & Bhatnagar, A., 2009. The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification. Drug Metabolism Review, 40(1), pp.553–624.
Das, S. et al., 2013. Anti-Cancer Potential of All trans-Retinoic Acid: A Review. Proceedings of the Zoological Society, 66, pp.1–7.
Hyndman, D. et al., 2005. The aldo-keto reductase superfamily homepage. Chemico-Biological Interactions, 143, pp.621–631.
Kansanen, E. et al., 2013. The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox Biology, 1(1), pp.45–49.
Matsunaga, T., El-kabbani, O. & Hara, A., 2013. Aldo-Keto Reductases as New Therapeutic Targets for Colon Cancer Chemoresistance B. Bonavida, ed. Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy, 1, pp.109–133. Available at: http://link.springer.com/10.1007/978-1-4614-7070-0 [Accessed October 18, 2013].
Mukherjee, S. et al., 2006. Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clinical Interventions in Aging, 1(4), pp.327–348. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699641/.
Ross, S.A. et al., 2003. Retinoids in Embryonal Development. Physiological Reviews, 80(3), pp.1021–1054.
Ruiz, F.X. & Porté, S., 2012. Biological Role of Aldo–Keto Reductases in Retinoic Acid Biosynthesis and Signaling. Frontiers in Pharmacology, 3(58), pp.321–334.