A research group led by Professor Yasuaki Kabe and Professor Makoto Suematsu (currently Chairman of AMED) of the Department of Medical Chemistry, Keio University School of Medicine is a membrane-bound heme protein that is highly expressed in many malignant tumors including intractable cancers. By elucidating the structure of a certain PGRMC1, he announced that he was the first in the world to clarify the mechanism by which cancer cells activate proliferation and the mechanism by which resistance to anticancer drugs is acquired.
In this study, we performed X-ray crystal structure analysis and clarified the detailed molecular structure of PGRMC1 for the first time in the world. PGRMC1 coordinates with heme in an unusual manner via tyrosine residues in the protein, and has a unique heme polymer structure in which hemes protruding on the protein surface are overlapped with almost no amino acid residues in the molecule. Is forming.In addition, biochemical analysis revealed that it exists as an apo body in a monomer structure in the absence of heme, and when it binds to heme, it becomes a dimer.Such a heme polymer structure is the first mode found in eukaryotes.CO, which is a gas molecule in the body, increases when cancer cells are exposed to anticancer drugs, radiation therapy, hypoxia, etc., but when this CO binds to the heme on PGRMC1, the polymerization between hemes dissociates. I found that the function of PGR MC1 disappeared.
In addition, the polymerized PGRMC1 associates with the receptor for epidermal growth factor (EGFR) involved in cancer growth to enhance the cancer growth signal, and also associates with the drug-metabolizing enzyme cytochrome P450 to anti-cancer. It was found that it enhances the degrading activity of cancer drugs and promotes drug resistance of cancer cells.
According to this study, PGRMC1 is activated by polymerizing in response to the heme concentration in cancer cells, and functions by dynamic structural transformation that is involved in promoting the growth of cancer cells and acquiring resistance to anticancer drugs. I made it clear that I was there.In addition, if a compound that binds to PGRMC1 and inhibits its function is found, it may lead to the development of new anticancer drugs.