Copper Metabolism Directly Influences Kinase Functionality To Modulate Signal Transduction In Cancer

Tiffany Tsang, University of Pennsylvania

Abstract

Copper (Cu) is an essential micronutrient involved in a myriad of fundamental biological processes. The importance of Cu in growth and development can be seen in rare genetic disorders manifested by a disruption in Cu homeostasis. However, the known repertoire of cuproproteins do not fully explain the growth defects observed. A new class of cuproproteins has emerged that consists of protein kinases. While traditionally viewed as a static cofactor, Cu is now appreciated as a dynamic regulator of signaling processes. The first Cu-dependent kinases identified were MEK1/2, linking Cu directly to the control of cell proliferation, apoptosis, survival, differentiation, motility, and metabolism through the MAPK pathway. Here, we identify autophagy kinases ULK1/2 and Hippo signaling kinases LATS1/2 as additional Cu-dependent kinases. Specifically, further analysis revealed that Cu is required for ULK1/2 kinase activity and that the depletion of Cu can blunt autophagy. Moreover, in the context of autophagy-dependent lung adenocarcinomas driven by KRASG12D or BRAFV600E, we identified that Cu depletion or disruption of ULK1-Cu binding dampened autophagy and decreased tumor growth. ULK1/2 Cu regulation may present a new therapeutic opportunity to target autophagy in cancers. In efforts to identify other Cu-dependent kinases and specifically those that may render limitations to Cu chelation therapy, we found that core kinases within the Hippo pathway, tumor suppressors LATS1/2, also bind to and are influenced by the Cu availability. Unlike Cu regulation of MEK1/2 and ULK1/2 in an oncogenic capacity, the Cu-dependent LATS1/2 kinase activity suggests that Cu chelation may result in activation of oncogenic transcriptional coactivators YAP/TAZ in facilitating the expression of genes associated with growth and survival. Here, we identified that Cu chelation combined with YAP suppression or treatment with YAP inhibitor, verteporfin, further suppressed growth and enhanced apoptosis in BRAFV600E-driven melanoma cells. These findings identify a new combination strategy to enhance the durability of Cu chelation. Taken together, the identification of ULK1/2 and LATS1/2 as Cu-responsive signaling molecules further define the contribution of Cu to cell growth and this newfound understanding reveals new therapeutic opportunities for Cu chelation that can be leveraged for the treatment of cancers.