Chemoresistance and Metastasis

Metastasis Chemoresistance

Iron is a critical component in oncogenesis due to its roles in cell cycle progression, DNA synthesis, and proliferation. However, under conditions of aberrant metal exposure, a link between high cellular iron levels and down-regulation of key tumor and metastasis suppressors has been observed. A recent report has provided the first crystallographic evidence for another contributing factor in cancer cell proliferation and metastatic processes – dimerization of the heme-containing protein progesterone-receptor membrane component 1 (PGRMC1).The heme-mediated dimerization of PGRMC1 enables interaction with the epidermal growth factor receptor (EGFR), has been shown to inhibit drug metabolism and even resulted in enhanced chemoresistance in several cancer cells including endometrial tumor, ovarian and breast cancer. The balance between normal, healthy cells and the deleterious effects associated with PGRMC1 heme binding and dimerization must rely on a precisely tuned coordination environment. In order to better understand this, our lab is utilizes a metal-centric approach to define and monitor perturbations at the metal-binding site in PGRMC1 and similar metal-dependent proteins associated with chemoresistance.