Targeting Copper Metabolism in Cancer: A Promising Therapeutic Strategy from Research to the Clinic
Targeting Copper Metabolism in Cancer: A Promising Therapeutic Strategy from Research to the Clinic
Amir Razmara,1Sara Abbasi,2Issa Layali,3Pezhman Shafiei Asheghabadi,4,*
1. 1 Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. 4 Biology Association, Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. 2. 1 Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. 4 Biology Association, Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. 3. 1 Department of Biochemistry and Biophysics, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. 2Biology Association, Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. 4. 1Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran 2Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
Introduction: According to the statistics of the World Health Organization (WHO), cancer is one of the main causes of death in the world. Aggressive and metastatic cancers show increased metabolic flexibility, so altered metabolism is one of the main characteristics of cancer cells. In this study, we describe the role of copper in signaling and metabolic pathways involved in cancer tumor growth and spread.
Methods: In order to obtain the most recent research, It was conducted an extensive search in PubMed and Google Scholar databases from 2020 to 2024 and identify 21 articles related to our main topic. The targeted searches included “Cancer”, “Cuproptosis”, “Copper”, “Signaling” and “Tumor”.
Results: Many human cells self-destruct and undergo apoptosis to maintain biological homeostasis, but one of the main characteristics of cancer cells is the escape from programmed death (apoptosis), which causes resistance. Chemical and cancer recurrence. Much research has focused on the alternative processes of cancer cell death, namely necroptosis, pyroptosis, ferroptosis, and coproptosis. Copper is a rare element in the body and is related to various signaling pathways involved in tumor growth and spread. It is also known that excess copper can lead to cell death. In fact, excess copper leads to the accumulation of dihydrolipoamide lipoyl S-acetyltransferase (DLAT), which is linked to the TCA cycle, leading to proteotoxic stress and the development of a new cell death method known as coproptosis. A targeted cancer treatment strategy is considered. Coproptosis also modulates antitumor immunity, therefore, understanding the mechanisms involved in modulating copper metabolism and coproptosis may facilitate improved cancer management. Copper plays an important role in receptor tyrosine kinase signaling pathways, which can bind and phosphorylate receptor tyrosine kinase (RTK) without ligand binding, leading to RKT activation. The activated RTK subsequently leads to the phosphorylation of downstream extracellular regulated protein kinases (ERK) and agammaglobulinemia tyrosine kinase (ATK) and ultimately leads to cell proliferation. It has also been suggested that copper ions probably activate downstream proteins by acting on different molecules of the phosphoinositide-3-kinase (PI3K)-AKT signaling pathway. On the one hand, copper can directly activate PI3K, leading to the downstream activation of AKT. On the other hand, copper binds to histidine 117 and histidine 203 of pyruvate dehydrogenase kinase 1 (PDK1), which leads to the activation of AKT. AKT activation induced by copper can catalyze the phosphorylation and intracellular redistribution of frontal box O1a (FoxO1a) and frontal box O4 (FoxO4), which promotes cancer cell proliferation and tumor growth.
Conclusion: Coproptosis is a type of copper-dependent cell death and has unique characteristics compared to other forms of cell death, which refers to the mitochondrial pathway of cell death and is caused by excessive copper exposure and subsequent proteotoxic stress. Aberrant copper metabolism has a dual role in tumorigenesis and cancer treatment, so targeting copper metabolism can provide a promising therapeutic approach in cancer research.