Cellular units in a living organism are in constant metabolism of substances and energy, realized through signals. In general, signal transduction can be referred to the biochemical process of perception of a chemical signal, which initiates intracellular reactions. The key criterion for transduction is the presence of receptors in the cell — may be on the membrane surface or in the cytoplasm — to which an external initiator molecule attaches.
An important mission of signal transduction is to control and regulate gene expression in the body. Consequently, depending on the nature of the incoming signal, the cell can either suppress or initiate protein biosynthesis, and disruption of such regulation can have serious consequences in the context of proliferation, differentiation, or apoptosis. Damage to the signal induction mechanism in proto-oncogenes has the potential to lead to the development of cancer cells in tissues. One of the most important signal transduction pathways in the body is the Wnt pathway, which regulates cell differentiation during human embryonic development. Disruption of this pathway guarantees the development of cancers even in adults.
The Figure represents the canonical signal transduction for the repressed (left) and activated (right) states. Regardless of the phase, Wnt targets the β-catenin protein involved in the regulation of gene transcription. When Wnt does not interact with the LRP6 receptor, there is little β-catenin in the cytoplasm: this is due to a degradation complex. This complex includes casein kinase, glycogen synthase kinase, and APC proteins located around the Axin envelope. This molecular complex initiates phosphorylation of β-catenin followed by β-TrCP ubiquitination, leading to degradation by the proteasome. Upon “turning on,” the initiator Wnt ligand actively attaches to the membrane LRP6, resulting in activation of Dishevelled protein.
In turn, this process inhibits the activity of the degradation complex and β-TrCP. Consequently, β-catenin in excess freely penetrates the nucleus and activates transcription of “Wnt target genes” via TCF/LEF factors. Mutation in APC proteins is most important in developing colorectal cancer (Flanagan et al., 2019). In addition, it should be remembered that the activated state of the Wnt pathway can be both beneficial for embryonic development and detrimental in the case of cancer cell proliferation. Thus, Resveratrol, a natural flavonoid, can be used to inhibit cancer cell growth (Cilibrasi et al., 2017). Under its action, the binding of β-catenin to TCF is disrupted, and hence the transcription of growth factors is suppressed.
References
Cilibrasi, C., Riva, G., Romano, G., Cadamuro, M., Bazzoni, R., Butta, V.,… & Bentivegna, A. (2017). Resveratrol impairs glioma stem cells proliferation and motility by modulating the Wnt signaling pathway. PLoS One, 12(1), 1-8.
Flanagan, D. J., Vincan, E., & Phesse, T. J. (2019). Wnt signaling in cancer: not a binary ON: OFF switch. Cancer Research, 79(23), 5901-5906.
Ng, L. F., Kaur, P., Bunnag, N., Suresh, J., Sung, I. C. H., Tan, Q. H.,… & Tolwinski, N. S. (2019). WNT signaling in disease. Cells, 8(8), 826-831.