ST6GAL1 Drug Discovery to Combat Cancer
The number of cancer hallmarks has increased as the knowledge and understanding of the disease progress. As many of us already know, the basic characteristic is a mutation that causes uncontrollable cell growth causing a tumor. Cancer is truly a multi-step development that enables cells to survive, proliferate and metastasize. Other hallmarks of the disease include:1
- sustaining proliferative signaling
- evading growth suppressors
- resisting cell death
- enabling replicative immortality
- inducing angiogenesis
- activating invasion and metastasis
- reprogramming of energy metabolism
- evading immune destruction
- tumor microenvironment
- aberrant glycosylation including abnormal sialylation
Scientists have found an overabundance of sialyltransferases (STs) in cancers. This isn’t surprising as many of the necessary functions (cell-cell recognition, protein targeting, and cell adhesion) occurring in our bodies are carried out via sialylation. These same functions along with many others are negatively affected in cancer patients leading to tumor progression and metastasis.
Sialylation is a common reaction that is catalyzed by an ST enzyme with the goal of adding a sialic acid (monosaccharide) to a growing oligosaccharide forming a glycolipid or glycoprotein. There are multiple types of STs named based on the linkage and function. For example, Beta-galactoside alpha-2,6-sialyltransferase 1 (ST6Gal1) transfers a sialic acid from CMP-sialic acid to galactose-containing substrates.
ST6Gal1 Responsibility and Role in Cancer
ST6Gal1 overexpression has been observed in several types of cancers including lung, cervical, ovarian, pancreatic, breast and colon carcinoma. Additionally, it has been reported to promote cancer cell metastasis and inhibit cell death pathways; thereby, supporting cell survival and growth. Specifically, the elevated levels regulate FAS and AKT so that tumor cells are able to evade apoptosis. 1
Furthermore, ST6Gal1 is correlated with high tumor grade, metastasis, and reduced patient prognosis. 1,2 Increased levels of the glycosyltransferase have also been identified to allocate resistance to chemotherapeutic intervention. 2
ST6GAL1 Activity Assay
Researchers have already started discovering ST6Gal1 inhibitors in order to combat cancer; however, there is much to learn and even more potential for drug discovery. The Transcreener® AMP²/GMP² Assay is capable of detecting ST6Gal1 activity through direct detection of CMP. The enzyme converts CMP-sialic acid to sialic acid in order to create a galactose-containing substrate, forming CMP as a product that can be measured by using a specific antibody labeled with a fluorophore. This advantageous method can assist in the drug discovery that so many cancer patients and their loved ones are waiting for.
References
- Garnham R, Scott E, Livermore K, Munkley J. ST6GAL1: A key player in cancer (Review). Oncol Lett. 2019:983-989. doi:10.3892/ol.2019.10458 https://www.ncbi.nlm.nih.gov/pubmed/31423157
- Montgomery AP, Skropeta D, Yu H. Transition state-based ST6Gal1 inhibitors: Mimicking the phosphodiester linkage with a triazole or carbamate through an enthalpy-entropy compensation. Sci Rep. 2017;7(1):1-11. doi:10.1038/s41598-017-14560-0 https://www.nature.com/articles/s41598-017-14560-0
