Cope with copper: From copper linked mechanisms to copper-based clinical cancer therapies

Transition metal elements, such as copper, play diverse and pivotal roles in oncology. They act as constituents of metalloenzymes involved in cellular metabolism, function as signaling molecules to regulate the proliferation and metastasis of tumors, and are integral components of metal-based anticancer drugs. Notably, recent research reveals that excessive copper can also modulate the occurrence of programmed cell death (PCD), known as cuprotosis, in cancer cells. This modulation occurs through the disruption of tumor cell metabolism and the induction of proteotoxic stress. This discovery uncovers a mode of interaction between transition metals and proteins, emphasizing the intricate link between copper homeostasis and tumor metabolism. Moreover, they provide innovative therapeutic strategies for the precise diagnosis and treatment of malignant tumors. At the crossroads of chemistry and oncology, we undertake a comprehensive review of copper homeostasis in tumors, elucidating the molecular mechanisms underpinning cuproptosis. Additionally, we summarize current nanotherapeutic approaches that target cuproptosis and provide an overview of the available laboratory and clinical methods for monitoring this process. In the context of emerging concepts, challenges, and opportunities, we emphasize the significant potential of nanotechnology in the advancement of this field.

Cuproptosis: Harnessing Transition Metal for Cancer Therapy.

Copper is an essential micronutrient that serves as a cofactor for enzymes involved in diverse physiological processes, including mitochondrial energy generation. Copper enters cells through a dedicated copper transporter and is distributed to intracellular cuproenzymes by copper chaperones. Mitochondria are critical copper-utilizing organelles that harbor an essential cuproenzyme cytochrome c oxidase, which powers energy production. Mutations in copper transporters and chaperones that perturb mitochondrial copper homeostasis result in fatal genetic disorders. Recent studies have uncovered the therapeutic potential of elesclomol, a copper ionophore, for the treatment of copper deficiency disorders such as Menkes disease. Here we review the role of copper in mitochondrial energy metabolism in the context of human diseases and highlight the recent developments in copper therapeutics. 

Mitochondrial copper in human genetic disorders

Although transition metals constitute less than 0.1% of the total mass within a human body, they have a substantial impact on fundamental biological processes across all kingdoms of life. Indeed, these nutrients play crucial roles in the physiological functions of enzymes, with the redox properties of many of these metals being essential to their activity. At the same time, imbalances in transition metal pools can be detrimental to health. Modern analytical techniques are helping to illuminate the workings of metal homeostasis at a molecular and atomic level, their spatial localization in real time, and the implications of metal dysregulation in disease pathogenesis. Fluorescence microscopy has proven to be one of the most promising non-invasive methods for studying metal pools in biological samples. The accuracy and sensitivity of bioimaging experiments are predominantly determined by the fluorescent metal-responsive sensor, highlighting the importance of rational probe design for such measurements. This review covers activity- and binding-based fluorescent metal sensors that have been applied to cellular studies. We focus on the essential redox-active metals: iron, copper, manganese, cobalt, chromium, and nickel. We aim to encourage further targeted efforts in developing innovative approaches to understanding the biological chemistry of redox-active metals.

Small-Molecule Fluorescent Probes for Binding- and Activity-Based Sensing of Redox-Active Biological Metals.

Christianity emerged as a small and marginal movement in the first century Palestine and throughout the following three centuries it became highly visible in the whole Mediterranean. Little is known about the mechanisms of spreading innovative ideas in past societies. Here we investigate how well the spread of Christianity can be explained as a diffusive process constrained by physical travel in the Roman Empire. First, we combine a previously established model of the transportation network with city population estimates and evaluate to which extent the spatio-temporal pattern of the spread of Christianity can be explained by static factors. Second, we apply a network-theoretical approach to analyze the spreading process utilizing effective distance. We show that the spread of Christianity in the first two centuries closely follows a gravity-guided diffusion, and is substantially accelerated in the third century. Using the effective distance measure, we are able to suggest the probable path of the spread. Our work demonstrates how the spatio-temporal patterns we observe in the data can be explained using only spatial constraints and urbanization structure of the empire. Our findings also provide a methodological framework to be reused for studying other cultural spreading phenomena.

Spatial constraints on the diffusion of religious innovations: The case of early Christianity in the Roman Empire

Significance Copper sustains fundamental chemical processes across all kingdoms of life by cycling between two major oxidation states, Cu(I) and Cu(II). However, in contrast to advances in fluorescent sensors and related probes to help decipher Cu(I) biology, Cu(II) detection remains lacking. We present a strategy using metal-directed acyl imidazole chemistry to enable both metal and oxidation state-specific Cu(II) detection by a tandem activity-based sensing/labeling reaction. We use this platform to identify the existence of loosely bound, labile Cu(II) pools, a Cu(II) import protein in cells, and reciprocal Cu(II) elevations and Cu(I) deficiencies driven by a loss of antioxidant defense in cellular models of cancer.

Oxidation state-specific fluorescent copper sensors reveal oncogene-driven redox changes that regulate labile copper(II) pools

Historical Atlas of Ancient Christianity ed. by Angelo Di Berardino, Gianluca Pilara (review)

PERK is a transmembrane kinase located on the ER with a luminal domain that senses ER stresses, such as protein misfolding, and a cytosolic kinase domain. Upon stress sensing, PERK activates and phosphorylates eIF2α to attenuate global translation while upregulating select transcripts to re-establish protein homeostasis. In a secondary phase of signaling PERK can also induce apoptosis to dispose of terminally stressed and damaged cells. Thus, the delineated bi-phasic nature of PERK signaling requires tight regulation for homeostatic function, as evidenced by dysregulation of this pathway being implicated in many diseases, including cancers and neurodegenerative conditions. Pursuant attempts to therapeutically modulate PERK and its signaling outcomes have highlighted that our understanding of the determinants of adaptive vs. mal-adaptive signaling remain ambiguous, and further delineation of PERK regulation is required. Here we report copper as a regulator of PERK kinase activity. PERK copper binding activity was confirmed by selective affinity for a copper charged resin and by ICP-MS quantification of bound copper. Mutation of the putative copper binding site, identified based on homology, abolished copper binding. Copper-binding was also determined to be necessary for kinase activity in in vitro kinase assays. Physiologic manipulation of copper availability in cells modulated PERK activity and signaling. Using this relationship, we show that copper availability determines ER stress tolerance and cell fate outcomes. This novel regulatory mechanism has broad implications for modulation of PERK activity in different diseases and disease models, and may constitute a previously unaccounted for variable in determining when PERK inhibition vs activation is therapeutically beneficial.

Copper as a Novel Regulator of PERK

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Oxidation state-specific fluorescent copper sensors reveal oncogene-driven redox changes that regulate labile copper(II) pools

Historical Atlas of Ancient Christianity ed. by Angelo Di Berardino, Gianluca Pilara (review)

Copper as a Novel Regulator of PERK