Anaphase Promoting Complex in Cancer

APC and Cancer

The main function of APC, which stands for anaphase promoting  complex, is to regulate the cell cycle at certain checkpoints, such as the G1 and M, and also allow the cell to exit mitosis. The Anaphase Promoting Complex is a multisubunit ubiquitin-protein ligase, meaning it helps regulate the cell cycle by breaking down proteins such as cyclin, which allows the cell to pass the checkpoints. There are about 12 subunits of APC which are all very important to its function by binding to different proteins and starting different signal trasnduction pathways.  APC regulates cyclin at G1 to make sure the cell correctly enters into the S phase where it copies the DNA. If there is enough cyclin the cell will enter into S phase. It then enables the cell to go into anaphase by breaking down the proteins holding the sister chromatids together. Once these proteins are broken down the cell chromatids can separate and go into anaphase. Activation of CDK is needed as well for the APC subunit CDC20 to break down the proteins holding together the chromatids. Inactivation of CDK activates the APC subunit CDH1 which breaks down cyclin so that the cell can exit out of mitosis. APC subunits coordinate with many other kinases to be either activated or inactivated.

            Oncogenes are viral genes that trigger cancerous characteristics in cells.  However, versions of these genes called proto-oncogenes are found in normal cells. All known proto-oncogenes code for proteins that affect the cell cycle, such as APC. Tumor virus’s can turn on or increase the number of proto-oncogenes transforming it into a cancerous cell. Proto-oncogenes can be turned cancerous in three main ways. One way is the movement of DNA within a genome. This may increase transcription in the gene.  Another way is amplification of the proto-oncogene, which can happen when there is an excess of normal growth stimulating proteins.  Lastly, there can be point mutation which is a gene that makes the proto-oncogenes protein product either more active or resistant to degradation than a normal protein. Oncogenes lead to an increase in either the amount of the proto-oncogene’s protein product or the intrinsic activity of each protein molecule. Many mutations have been found in APC and many of these mutations have a role in cancer.  Mutations in the subunits APC6/CDC16, APC8/CDC23 and APC3/CDC27 have had connections with colon cancer, breast cancer, neuroblastoma, ovarian carcinoma and more. One mutation with a deleted adenine nucleotide results in a premature stop codon. It has also been shown that malignant tumors show misregulation of the APC/C that is not seen in benign tumors. Dysfunctions with the APC-CDH1 during the G1/S checkpoint showed that a large number of mitotic factors critical for passing the checkpoint  such as cyclin B1 were unable to accumulate. However, other activities needed for DNA replication were increased through the increase of E2F-dependent cyclin E transcription. APC is also needed for the cell to exit mitosis and go into cytokinesis, so inactivation of the APC after the S checkpoint slowed down the ability of the cell to divide but allowed the DNA to slowly, but surely keep replicating, creating a massive genome.         

While APC has been accused for causing cancer, there is also research going into using APC to treat cancer. Certain viral proteins can be used to interact with APC and inhibit it causing cell apoptosis along with cytoxicity specifically in tumor cells which suggests APC could be used to stop these tumors from growing.