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

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Abstract

Recent studies have established a strong link between copper and cancer biology, as copper is necessary for cancer growth and metastasis. Beyond the conventional concept of copper serving as a catalytic cofactor of metalloenzymes, emerging evidence demonstrates copper as a regulator for signaling transduction and gene expression, which are vital for tumorigenesis and cancer progression. Interestingly, strong redox-active properties make copper both beneficial and detrimental to cancer cells. Cuproplasia is copper-dependent cell growth and proliferation, whereas cuproptosis is copper-dependent cell death. Both mechanisms act in cancer cells, suggesting that copper depletion and copper supplementation may be viable approaches for developing novel anticancer therapies. In this review, we summarized the current understanding of copper's biological role and related molecular mechanisms in cancer proliferation, angiogenesis, metastasis, autophagy, immunosuppressive microenvironment development, and copper-mediated cancer cell death. We also highlighted copper-based strategies for cancer treatment. The current challenges of copper in cancer biology and therapy and their potential solutions were also discussed. Further investigation in this field will yield a more comprehensive molecular explanation for the causal relationship between copper and cancers. It will reveal a series of key regulators governing copper-dependent signaling pathways, thereby providing potential targets for developing copper-related anticancer drugs.

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Ferroptosis: mechanisms, biology and role in disease

Xuejun Jiang, Brent Stockwell, Marcus Conrad (2021)

The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.

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The Warburg Effect: How Does it Benefit Cancer Cells?

Maria Liberti, Jason Locasale (2016)

Cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance. The common feature of this altered metabolism is the increased glucose uptake and fermentation of glucose to lactate. This phenomenon is observed even in the presence of completely functioning mitochondria and, together, is known as the 'Warburg Effect'. The Warburg Effect has been documented for over 90 years and extensively studied over the past 10 years, with thousands of papers reporting to have established either its causes or its functions. Despite this intense interest, the function of the Warburg Effect remains unclear. Here, we analyze several proposed explanations for the function of Warburg Effect, emphasize their rationale, and discuss their controversies.

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Copper induces cell death by targeting lipoylated TCA cycle proteins

Peter Tsvetkov, Shannon Coy, Boryana Petrova … (2022)

Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms. Cell death is an essential, finely tuned process that is critical for the removal of damaged and superfluous cells. Multiple forms of programmed and nonprogrammed cell death have been identified, including apoptosis, ferroptosis, and necroptosis. Tsvetkov et al . investigated whether abnormal copper ion elevations may sensitize cells toward a previously unidentified death pathway (see the Perspective by Kahlson and Dixon). By performing CRISPR/Cas9 screens, several genes were identified that could protect against copper-induced cell killing. Using genetically modified cells and a mouse model of a copper overload disorder, the researchers report that excess copper promotes the aggregation of lipoylated proteins and links mitochondrial metabolism to copper-dependent death. —PNK Lipoylation determines sensitivity to copper-induced cell death.