Understanding The Mechanism Of Cancer Therapeutic EJ1-SAH5 In Targeting Breast Cancer Metastasis
AuthorSoyfer, Eli Michael
AdvisorSchroeder, Joyce A.
MetadataShow full item record
PublisherThe University of Arizona.
AbstractA key oncogene in breast cancer is the receptor tyrosine kinase EGFR (epidermal growth factor receptor). This protein is responsible, among other things, excessive proliferation and survival (evasion of apoptosis). In breast cancer cells, EGFR’s translocation to the nucleus causes resistance to cancer therapeutics. This has led to the field of research in cancer therapies that can target and inactivate EGFR, preventing its promotion of the breast cancer phenotype. Previous therapeutics, such as the tyrosine kinase inhibitors lapatinib and afatinib, and tyrosine kinase inhibitors that target the kinase domain of EGFR, have been found to have minimal effect when used to treat breast cancer. Therefore, another method of targeting EGFR via its JXM domain has been developed. This drug is known as SAH5-EJ1. Prior research has established that SAH5-EJ1 binds to a region of EGFR, the juxtamembrane (JXM) domain, causing reduced cell viability, inhibited ERBB activation, modified Calcium/Calmodulin signaling to promote membrane blebbing, stimulated ROS production in the mitochondria, and overall causing apoptosis and necrosis in TNBC (triple negative breast cancer) cells. To determine a potential source of calcium that is caused by the use of SAH5, different assays have been done to determine which calcium channels act as drivers. MTT assays have shown that the mechanism of SAH5-induced cell death doesn’t involve the IP3 receptor (as seen when SAH5-induced cell death still happens in the presence of IP3R inhibitor 2-APB). Also, a rescue effect from SAH5-induced cell death could be seen via use of the antioxidant NAC, or the combination of reduced glutathione (GSH) and a thiol (RSH), the downstream products of NAC. This is further seen in how using either BCTC, NAC, or a combination of both on SAH5-treated TNBC cells results in a drop in ROS (reactive oxygen species) in these cells. Finally, there is data to suggest the mechanism of action for SAH5 involves the use of the calcium membrane transporter TRPV1, whose inhibition lowers the effects of SAH5-induced cell death. Overall, the current data suggests that SAH5 is a potent cancer therapeutic in TNBC and its mechanism of action involves the use of membrane transporter TRPV1.