Copper metabolism and cuproptosis in human malignancies: Unraveling the complex interplay for therapeutic insights.

Copper, a vital trace element, orchestrates diverse cellular processes ranging from energy production to antioxidant defense and angiogenesis. Copper metabolism and cuproptosis are closely linked in the context of human diseases, with a particular focus on cancer. Cuproptosis refers to a specific type of copper-mediated cell death or copper toxicity triggered by disruptions in copper metabolism within the cells. This phenomenon encompasses a spectrum of mechanisms, such as oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and perturbations in metal ion equilibrium. Mechanistically, cuproptosis is driven by copper binding to the lipoylated enzymes within the tricarboxylic acid (TCA) cycle. This interaction participates in protein aggregation and proteotoxic stress, ultimately culminating in cell death. Targeting copper metabolism and its associated pathways in cancer cells hold therapeutic potential by selectively targeting and eliminating cancerous cells. Strategies to modulate copper levels, enhance copper excretion, or interfere with cuproptotic pathways are being explored to identify novel therapeutic targets for cancer therapy and improve patient outcomes. Understanding the relationship between cuproptosis and copper metabolism in human malignancies remains an active area of research. This review provides a comprehensive overview of the association among copper metabolism, copper homeostasis, and carcinogenesis, explicitly emphasizing the cuproptosis mechanism and its implications for cancer pathogenesis. Additionally, we emphasize the therapeutic aspects of targeting copper and cuproptosis for cancer treatment.

ASPORIN: A root of the matter in tumors and their host environment.

Asporin (ASPN) has been identified as one of the members of the class I small leucine-rich proteoglycans (SLRPs) family in the extracellular matrix (ECM). It is involved in classic ensigns of cancers such as self-dependent growth, resistance to growth inhibitors, restricting apoptosis, cancer metastasis, and bone-related disorders. ASPN is different from other members of SLRPs, such as decorin (DCN) and biglycan (BGN), in a way that it contains a distinctive length of aspartate (D) residues in the amino (N) -terminal region. These D-repeats residues possess germline polymorphisms and are identified to be linked with cancer progression and osteoarthritis (OA). The polyaspartate stretch in the N-terminal region of the protein and its resemblance to DCN are the reasons it is called asporin. In this review, we comprehensively summarized and updated the dual role of ASPN in various malignancies, its structure in mice and humans, variants, mutations, cancer-associated signalings and functions, the relationship between ASPN and cancer-epithelial, stromal fibroblast crosstalk, immune cells and immunosuppression in cancer and other diseases. In cancer and other bone-related diseases, ASPN is identified to be regulating various signaling pathways such as TGFß, Wnt/ß-catenin, notch, hedgehog, EGFR, HER2, and CD44-mediated Rac1. These pathways promote cancer cell invasion, proliferation, and migration by mediating the epithelial-to-mesenchymal transition (EMT) process. Finally, we discussed mouse models mimicking ASPN in vivo function in cancers and the probability of therapeutic targeting of ASPN in cancer cells, fibrosis, and other bone-related diseases.