Cyclophilin A (CypA), a protein from the immunophilin family, is believed to have a role in the increase of human cancers. CypA is thought to be influential in cancer metastasis, the movement of the disease from one organ to another. However, not much is known about the mechanism that the protein uses to carry out its activities.
Studies have shown that CypA is abundant when cancer is present and decreases when anti-cancer medicines are used. CypA is reduced when the drug cyclosporine (CsA) is taken or small interfering RNA (siRNA) are present. A Bruker 700 MHz NMR spectrometer was recently used to identify that CsA suppresses the immune system and reduces the risk of cancer simultaneously through binding with the reactive site in CypA.
CsA is usually used in organ transplant patients such as the kidney, heart or liver, to lower the immune system’s resistance to a new organ. The immune system is designed to fight off any sign of disturbance or potential attack when it is functioning properly, this includes cells that it identifies as foreign such as bacteria, viruses and so forth. The immune system often identifies a new organ as a threat as the cells are different from its own.
Tissue typing of humans is carried out by medical staff to help them find the best available donor match for a patient who needs an organ transplant. It is rare that a drug is not needed to help the patient accept an organ from someone else; this typically only happens with identical twins.
Post-transplant, the patient has to use the immune suppressant drug for the rest of his or her life or else the body’s immune system will automatically kick into action and start to reject the organ and put the patient’s life at risk.
As a consequence of the lowered immune system, transplant patients have a greater risk of cancer. However, the cancer risk does not appear to be as significant when CsA is used. Scientific researchers Tamjeed Saleh et al. investigated the mechanisms.
The human body has Crk adaptor proteins which exist in tissues but are overexpressed in cancer tumors. Their levels in a tumor help to indicate the stage of cancer in a patient. The role of these proteins is to change the way that a cell behaves such as its metabolic rate and cell expression. Cancer cells have a different metabolism to other cells. CrkII are active in facilitating the kinase Abl in the body to trigger the development of chronic myelogenous leukemia.
The binding area of CrkII is identified as Gly219-Pro220. When the Gly219-Pro220 area of CrkII is swapped with alanine, the CypA and CrkII do not bind. When CsA is added CrkII does not bind with CypA as CsA and CypA prefer to bind with one another.
NMR spectrometry helped to confirm the structures of the molecules involved in the various stages of the processes. The experiment illustrated that the Abl-Crk signalling pathway could be disrupted with the use of CsA.
References:
Saleh, Tamjeed et al. Cyclophilin A promotes cell migration via the Abl-Crk signaling pathway. Nature Chemical Biology 12, 117-123 (2016) doi:10.1038/nchembio.1981 http://www.nature.com/nchembio/journal/v12/n2/full/nchembio.1981.html
Wang P and Heitman J. The cyclophilins. Genome Biol. 2005; 6(7): 226 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1175980/
Schaller MD. Paxillin: a focal adhesion-associated adaptor protein. Oncogene 2001 Oct 1;20(44):6459-72 http://www.ncbi.nlm.nih.gov/pubmed/11607845
Liu, D. The adaptor protein Crk in immune response. Immunology and Cell Biology (2014) 92, 80-89 doi:10.1038/icb.2013.64 http://www.nature.com/icb/journal/v92/n1/full/icb201364a.html
Bruker TCI CryoProbe: https://www.bruker.com/products/mr/nmr/probes/cryoprobes/tci-cryoprobe/overview.html
Information on the drug Cyclosporine: https://www.nlm.nih.gov/medlineplus/druginfo/meds/a601207.html#why
Transplant rejection: https://www.nlm.nih.gov/medlineplus/ency/article/000815.htm
Arthritis Research UK: http://www.arthritisresearchuk.org/arthritis-information/conditions/rheumatoid-arthritis/what-is-rheumatoid-arthritis.aspx
Principles of NMR via Imperial College: http://www.ch.ic.ac.uk/local/organic/nmr_principles.html