COMMD3 mediates melanin synthesis through both clusterin-PAX3 axis and copper-dependent tyrosinase activity in skin pigmentation.

Wilson disease

Histamine Induces Melanogenesis and Morphologic Changes by Protein Kinase A Activation via H2 Receptors in Human Normal Melanocytes

Skin, our first interface to the external environment, is subjected to oxidative stress caused by a variety of factors such as solar ultraviolet, infrared and visible light, environmental pollution, including ozone and particulate matters, and psychological stress. Excessive reactive species, including reactive oxygen species and reactive nitrogen species, exacerbate skin pigmentation and aging, which further lead to skin tone unevenness, pigmentary disorder, skin roughness and wrinkles. Besides these, skin microbiota are also a very important factor ensuring the proper functions of skin. While environmental factors such as UV and pollutants impact skin microbiota compositions, skin dysbiosis results in various skin conditions. In this review, we summarize the generation of oxidative stress from exogenous and endogenous sources. We further introduce current knowledge on the possible roles of oxidative stress in skin pigmentation and aging, specifically with emphasis on oxidative stress and skin pigmentation. Meanwhile, we summarize the science and rationale of using three well-known antioxidants, namely vitamin C, resveratrol and ferulic acid, in the treatment of hyperpigmentation. Finally, we discuss the strategy for preventing oxidative stress-induced skin pigmentation and aging.

The synthesis and distribution of melanin in the skin, hair bulbs and eyes determine the visible pigmentation of mammals (1,s1). The melanin within the melanosomes is synthesized by melanocytes and uncontrolled production or the abnormal distribution of melanin can cause hyperpigmentation, which is associated with several skin disorders, such as melasma and age spots (2,s2). Melanin synthesis is regulated by the tyrosinase gene family, which consists of tyrosinase, tyrosinase-related protein 1 (Tyrp1) and tyrosinase-related protein 2 (Tyrp2) that are specifically expressed in melanocytic cells. Tyrosinase is a rate-limiting enzyme in melanin biosynthesis 3. The microphthalmia-associated transcription factor (MITF), related with melanocyte survival and proliferation, is known to be a key regulator of tyrosinase, Tyrp1 and Tyrp2 (s3–s5). Because tyrosinase is the key to melanin production, many agents have been evaluated for their ability to suppress tyrosinase function or melanin synthesis by melanocytes to treat a variety of hyperpigmentary disorders and skin whitening (2, 3,s6). A chalcone was purified from an extract of Psoralea corylifolia, and the structure was identified as 4-hydroxylonchocarpin (HLCP) (4,s7). HLCP has been reported to have diverse pharmacological activities, including antibacterial, antifungal, anticancer, antireverse transcriptase, antitubercular, antimalarial, anti-inflammatory, ornithine decarboxylase and antioxidant activities 5. However, the effects of HLCP on melanogenesis are not known. In this study, we report on the antimelanogenic activity of HLCP in melanoma cells and the mechanisms involved in the inhibitory activity. In previous study in our laboratory, a chalcone compound was purified from the extracts of Psoralea corylifolia based on its antimelanogenic activity and identified as 4-hydroxylonchocarpin (HLCP). HLCP has been shown to have several pharmacological activities. In this study, we investigated whether HLCP affects melanogenesis by assaying tyrosinase synthesis and activity in mouse and human melanoma cells. We used three different melanoma cell lines: B16F10 mouse melanoma, SKMEL-2 and MNT-1 human melanoma cell lines. First, to verify whether HLCP affects phenotypes of melanoma, tyrosinase activity and pigmentation of cell pellets were investigated. Next, using western blot analysis, tyrosinase and MITF expression was observed. Finally, we analysed AKT/GSK and MAPK signalling pathways, which are involved in melanogenesis through MITF phosphorylation and expression, and investigated whether the activation of these kinases affects melanogenesis using MAPK inhibitors. Compound 2 was obtained from the EtOAc soluble fraction of P. corylifolia, through several steps. Its structure was confirmed to be 4-hydroxylonchocarpin (HLCP) 4 (Fig. S1A). We found non-toxic concentration of HLCP in B16F10 cells within 48 h using MTT assay (Fig. S1B). When we performed tyrosinase activity assay using B16F10 cell line, L-DOPA oxidation was dose-dependently reduced between HLCP concentrations of 7.5–30 μm (Fig. S1C). When compared with arbutin, which known as a melanogenesis inhibitor (s8,s9), HLCP was able to inhibit tyrosinase activity in melanoma cells more effectively than arbutin at the lower concentration (Fig. S1D). Moreover, tyrosinase activities induced by α-MSH and IBMX, which are inducer of melanogenesis by increasing intra-cellular cAMP (6,s10,s11), were decreased by over 50% when combined with HLCP (Fig. 1a and b). In addition, the pigmentation of the cell pellets treated with IBMX or α-MSH was substantially decreased by cotreatment with HLCP. We performed western blot analysis to determine whether the tyrosinase inhibition by HLCP is caused by the modulation of tyrosinase expression. The expression of tyrosinase induced by IBMX or α-MSH was significantly reduced (Fig. 1c and d). We confirmed these results using RT-qPCR (Fig. S2A) and found that expression of Tyrp1 and Dct/Tyrp2 was downregulated even in the presence of IBMX (Fig. S2B and S2C). MITF expression at the protein and mRNA level was reduced by HLCP (Fig. 1e–f and S2D). Furthermore, MITF and tyrosinase expression in SKMEL and MNT-1 human melanoma cell lines was also significantly reduced by HLCP (Fig. S3). In accordance with our RT-qPCR results, HLCP inhibited the promoter activity of tyrosinase and MITF (Fig. S4A–S4D). It is well known that melanogenesis is affected by MITF regulation through several pathways, such as Wnt, phosphatidylinositol-3-kinse (PI3K)/AKT and MAPK signalling pathways. Activation of GSK3β by intra-cellular cAMP, through the inhibition of PI3K/AKT, induces MITF stability and melanogenesis 7. We noted a decrease in AKT and GSK3β phosphorylation due to IMBX and α-MSH treatment and found that the phosphorylation was reversed after HLCP cotreatment (Fig. 2a and b). Moreover, p38 MAPK, ERK and JNK also participate in melanogenesis through MITF phosphorylation and expression (8,s12-14). Thus, we performed western blot analysis to examine whether HLCP affects MITF regulation via the activation of these kinases. Interestingly, phosphorylation of p38 MAPK, JNK and ERK was increased by HLCP, but not arbutin (Fig. 2c). We also observed phosphorylation of AKT, p38 MAPK, JNK and ERK by HLCP in SKMEL-2 and MNT-1 cells (Fig. S5A and S5B). Remarkably, arbutin did not affect both pathway, indicating differential mechanisms by which arbutin and HLCP exert their antimelanogenic effect. To investigate whether the activation of these kinases affects melanogenesis, we treated the cells with each of the following inhibitors: PD98059 (ERK inhibitor), SB203580 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor). As expected, the pigmentation of the cell pellets was increased by these inhibitors (Fig. 2d), indicating that they do enhance melanogenesis. However, the combination of inhibitor and HLCP abolished the pigmentation induced by the kinase inhibitors. It has been reported that elevated levels of cAMP lead to the induction of MAPK phosphatases-1 (MKP-1), which is known to be responsible for the inactivation of ERK, JNK and p38 MAPK (9,s15). Thus, we investigated whether HLCP inhibits MKP-1, leading to the elevated phosphorylation of these kinases. As shown in Fig. 2(e), the phosphorylation of ERK, JNK and p38 MAPK occurred in parallel with the decrease in MKP-1 expression caused by HLCP treatment. These findings demonstrate that, in contrast to arbutin, HLCP likely inhibits MITF activity by inducing AKT/GSK3β, p38 MAPK, JNK and ERK signalling. Collectively, the data suggest that HLCP inhibits melanogenesis through the inhibition of melanogenic enzymes and MITF expression as well as activity. We found that the antimelanogenic effects of HLCP are best explained by the inhibition of MITF expression and inactivation of its downstream target genes, such as tyrosinase, Tyrp1 and Dct, and through the suppression of MKP-1. Our findings reveal that HLCP may be useful therapeutically and cosmetically for several hyperpigmentary skin disorders, such as melasma and age spots, as well as skin whitening. This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Ministry of Science, ICT and Future Planning (2011-0030074, 2012R1A2A2A01046114 and 2014R1A2A2A09052492). J. Lim, J.-H. Ryu and J.-S. Lim designed experiments and wrote the manuscript. J. Lim and S. Nam performed experiments. J.-H. Ryu and J.-S. Lim analysed the data. Y. Yang, M.-S. Lee and H.G. Lee provided technical support. H. Li and J.-H. Ryu contributed to HLCP isolation and analysed its biochemical data. All of authors provided critical reviews of the manuscript. The authors have declared no conflict of interests. Figure S1. The effects of different concentrations of HLCP on cell viability and tyrosinase activity in B16F10 mouse melanoma cells. Figure S2. Inhibition of melanogenic enzymes and MITF expression by HLCP in B16F10 cells. Figure S3. Inhibition of MITF and tyrosinase expression by HLCP in SKMEL-2 and MNT-1 human melanoma cells. Figure S4. Inhibition of IBMX-induced tyrosinase and MITF promoter activities by HLCP in B16F10 cells. Figure S5. The effects of HLCP on AKT, ERK, JNK and p38 phosphorylation in SKMEL-2 and MNT-1 human melanoma cells. 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Post-Transcriptional Regulation of Melanin Biosynthetic Enzymes by cAMP and Resveratrol in Human Melanocytes

Copper ions play various roles in mammalian cells, presumably due to their involvement in different enzymatic reactions. Some studies indicated that serum copper correlates with fibrosis in organs, such as liver and lung. However, the mechanism is unknown. Here, we explored the role of copper in kidney fibrosis development and possible underlying mechanisms. We found that copper transporter 1 (CTR1) expression was increased in the kidney tissues in two fibrosis models and in patients with kidney fibrosis. Similar results were also found in renal tubular epithelial cells and fibroblast cells treated with transforming growth factor beta (TGF-β). Mechanistically, the upregulation of CTR1 required Smads-dependent TGF-β signaling pathway and Smad3 directly binded to the promoter of CTR1 in renal fibroblast cells using chromatin immunoprecipitation. Elevated CTR1 induced increase of copper intracellular influx. The elevated intracellular copper ions activated lysyl oxidase (LOX) to enhance the crosslinking of collagen and elastin, which then promoted kidney fibrosis. Reducing intracellular copper accumulation by knocking down CTR1 ameliorated kidney fibrosis in unilateral ureteral obstruction induced renal fibrosis model and renal fibroblast cells stimulated by TGF-β. Treatment with copper chelator tetrathiomolybdate (TM) also alleviated renal fibrosis in vivo and in vitro. In conclusion, intracellular copper accumulation plays a unique role to kidney fibrosis by activating LOX mediated collagen and elastin crosslinking. Inhibition of intracellular copper overload may be a potential portal to alleviate kidney fibrosis.

Cell culture studies of menkes kinky hair disease

Regulation of copper uptake and transport in intestinal cell monolayers by acute and chronic copper exposure

Background: Glioblastoma (GBM) is an aggressive primary brain tumor characterized by limited therapeutic options and poor prognosis. Temozolomide (TMZ) remains the standard chemotherapy; however, its effectiveness is often hindered by the development of acquired resistance. Cuproptosis, a recently identified copper-dependent form of regulated cell death, has emerged as a potential therapeutic target. The synergistic effects of TMZ and copper, as well as the molecular mechanisms underlying their combined action, remain unclear. This study aimed to investigate the role of tripartite motif-containing protein 14 (TRIM14) and its downstream effector ATP7A in mediating TMZ- and copper-induced cuproptosis in glioma. Methods: We employed in vitro cellular assays, in vivo xenograft models, bioinformatic analysis, immunofluorescence staining, Western blotting, and co-immunoprecipitation experiments to examine the functional involvement of TRIM14 and ATP7A during combined TMZ and copper chloride (CuCl2) treatment. Intracellular copper levels and cuproptosis markers, including Dihydrolipoamide S-acetyltransferase (DLAT), were assessed to evaluate copper-dependent cytotoxicity. Results: TMZ combined with CuCl2 markedly enhanced cuproptosis in glioma cells, as evidenced by increased DLAT expression and elevated intracellular copper accumulation. This combination treatment significantly suppressed TRIM14 expression, downregulated the TRIM14-ATP7A axis, and inhibited non-canonical NF-κB signaling. Co-immunoprecipitation assays further revealed a potential interaction between TRIM14 and ATP7A, suggesting that TRIM14 may modulate ATP7A stability or activity. Conclusions: Our findings indicate that TMZ and copper synergistically induce cuproptosis in GBM by disrupting the TRIM14-ATP7A regulatory axis and promoting intracellular copper accumulation. Targeting TRIM14 or ATP7A to enhance cuproptosis may represent a promising therapeutic strategy to overcome TMZ resistance and improve clinical outcomes in GBM patients.

Early diagnosis of late-onset Alzheimer's disease (AD) by peripheral biomarkers remains a challenge; many have been proposed, but none have been evaluated in a prospective manner. CLUSTERIN (CLU), a chaperone protein expressed in the brain and found in relatively high concentrations in plasma, is a promising candidate. CLU contributes to the elimination of β-amyloid (Aβ), which is associated to neurofibrillary tangles and to the genetic risk for AD. We performed a longitudinal measurement of CLU in the brain and the plasma in 3xTgAD mice. Assessment of CLU was also conducted in 12-month-old TgF344-AD rats. In humans, brain CLU was measured in non-demented and in AD subjects. The plasma CLU was longitudinally measured in four cohorts defined as healthy controls that remained stable, healthy controls that presented a cognitive decline between the two measures, mild cognitive impairment (MCI) that presented a cognitive decline between the two measures and AD. A validation cohort composed of 19 MCI was used and plasma CLU was measured before and after conversion in AD. Increases in CLU were measured in the hippocampus of 3xTgAD and TgF344-AD animals in the absence of plasmatic changes. CLU is heterogeneously expressed in the hippocampus in non-demented individuals and increased in AD. In the plasma, two CLU levels were measured: low in controls and MCI, and high in AD. To validate that the elevation in CLU is associated with conversion to AD, a replication study showed, in a second group MCI patients converting to AD in the follow-up that CLU levels increased in 16/19 individuals. The increase in brain CLU occurs in AD models as in humans, and seems to precede plasma variations, which could make it an AD therapeutic target. Plasma CLU seems to be a promising marker of cognitive decline, and its association with AD may be a useful complementary diagnostic tool.

Given the strong clinical evidence that copper levels are significantly elevated in a wide spectrum of tumors, copper homeostasis is considered as an emerging target for anticancer drug design. Monitoring copper levels in vivo is therefore of paramount importance when assessing the efficacy of copper-targeting drugs. Herein, we investigated the activity of the copper-targeting compound Dextran-Catechin by developing a [64Cu]CuCl2 PET imaging protocol to monitor its effect on copper homeostasis in tumors.Methods: Protein expression of copper transporter 1 (CTR1) in tissue microarrays representing 90 neuroblastoma patient tumors was assessed by immunohistochemistry. Western blotting analysis was used to study the effect of Dextran-Catechin on the expression of CTR1 in neuroblastoma cell lines and in tumors. A preclinical human neuroblastoma xenograft model was used to study anticancer activity of Dextran-Catechin in vivo and its effect on tumor copper homeostasis. PET imaging with [64Cu]CuCl2 was performed in such preclinical neuroblastoma model to monitor alteration of copper levels in tumors during treatment.Results: CTR1 protein was found to be highly expressed in patient neuroblastoma tumors by immunohistochemistry. Treatment of neuroblastoma cell lines with Dextran-Catechin resulted in decreased levels of glutathione and in downregulation of CTR1 expression, which caused a significant decrease of intracellular copper. No changes in CTR1 expression was observed in normal human astrocytes after Dextran-Catechin treatment. In vivo studies and PET imaging analysis using the neuroblastoma preclinical model revealed elevated [64Cu]CuCl2 retention in the tumor mass. Following treatment with Dextran-Catechin, there was a significant reduction in radioactive uptake, as well as reduced tumor growth. Ex vivo analysis of tumors collected from Dextran-Catechin treated mice confirmed the reduced levels of CTR1. Interestingly, copper levels in blood were not affected by treatment, demonstrating potential tumor specificity of Dextran-Catechin activity.Conclusion: Dextran-Catechin mediates its activity by lowering CTR1 and intracellular copper levels in tumors. This finding further reveals a potential therapeutic strategy for targeting copper-dependent cancers and presents a novel PET imaging method to assess patient response to copper-targeting anticancer treatments.

Rationale: Treatment of patients with triple-negative breast cancer (TNBC) remains challenging due to unpredictable disease progression and acquired resistance to chemotherapy. Finding novel targets in TNBC is important for the development of anticancer therapy. Cancer cells frequently adapt to cytotoxicity of existing pharmacological agents by exploiting metabolic pathways. Elevated copper metabolism and adaptations to oxidative stress have been linked to cancer progression. Copper chelation with tetrathiomolybdate (TM) was reported to control disease progression, especially in patients with TNBC. However, long-term consequences of global copper depletion are still under investigation. An alternative strategy is provided by a recently developed small molecule DCAC50 that blocks the copper transfer interface of two major copper chaperons, ATOX-1 and CCS. Protein levels of ATOX-1 and CCS are elevated in TNBC cells compared to normal cells. Thus, we hypothesized that disrupting copper transport by targeting ATOX-1 and CCS with DCAC50 may suppress TNBC progression. Results: We investigated efficacy and potency of novel small molecule DCAC50 to induce cytotoxicity in a panel of TNBC cells lines. DCAC50 reduced cell proliferation in dose-dependent manner, measured by MTS assay. IC50 doses ranged from 3-10uM. Most importantly, DCAC50 induced apoptosis in TNBC cells, detected by Caspase 3/7 activity and Annexin V/PI staining. As expected, DCAC50 elevated intracellular copper levels. Moreover, TNBC cells treated with DCAC50 had significantly higher levels of oxidized glutathione (GSSG) and caused increased oxidation of DCF-DA reagent, demonstrating elevated oxidative stress. Surprisingly, activity of CCS downstream target, SOD1, was not affected by selective inhibition of copper transport with DCAC50; suggesting that intracellular copper accumulation and oxidative stress is mediated by ATOX-1 inhibition. Interestingly, copper depletion with TM inhibited SOD1 activity but failed to significantly impact oxidative stress in TNBC cells. Recognizing DCAC50 generates oxidative stress triggering apoptosis in TNBC cells we evaluated benefits of combining DCAC50 treatment with paclitaxel. Multi-drug combination dose-response analysis revealed that co-treatment induced synergistic cytotoxicity and resulted in favorable dose reduction of both drugs. Conclusions: Selective inhibition of copper metabolism with novel small molecule DCAC50 elevates oxidative stress triggering apoptosis in TNBC cells. This approach may be valuable in combination with chemotherapy especially when tumor cells acquire resistance to first line therapy in TNBC. Ongoing studies comparing selective inhibition of copper transport to global copper chelation, and investigating efficacy and biological activity of DCAC50 in vivo will help further estimate benefits and clinical relevance of this approach for treatment of TNBC patients. Citation Format: Olga Karginova, Claire Weekley, Akila Raoul, Alhareth Alsayed, Tong Wu, Chuan He, Olufunmilayo I. Olopade. Selective inhibition of copper metabolism as a novel approach to treat triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3552. doi:10.1158/1538-7445.AM2017-3552

Cuproptosis is a copper-dependent form of regulated cell death with emerging relevance to cancer therapy. However, the upstream determinants of copper-associated cytotoxicity and cuproptosis-related sensitivity in gastric cancer remain incompletely defined. Using AGS gastric cancer cells with genetic gain- and loss-of-function of COX17 and p53, we assessed viability using CCK-8 assays, cell death using TUNEL staining, intracellular copper levels, migration and invasion using wound healing and Transwell assays, and the expression of copper handling and cuproptosis-associated proteins by Western blotting. The potential transcriptional regulation of COX17 by p53 was evaluated using ChIP-qPCR. Paracrine effects on angiogenesis-related phenotypes were evaluated in HUVECs exposed to tumor-cell-conditioned media, followed by tube formation, ROS, GSH, SOD, and MDA measurements. In vivo relevance was examined in a subcutaneous AGS xenograft model treated with elesclomol. COX17 alone had only a modest effect on basal cell viability but markedly increased the sensitivity of AGS cells to elesclomol-induced copper-associated cytotoxicity, accompanied by increased intracellular copper accumulation and TUNEL positivity, whereas COX17 knockdown attenuated these effects. Elesclomol treatment with COX17 modulation was associated with increased SLC31A1 expression and decreased ATP7A expression. p53 overexpression suppressed malignant phenotypes and increased COX17 expression. ChIP-qPCR showed the enrichment of p53 at the COX17 promoter region, suggesting that p53 may participate in the transcriptional regulation of COX17. Functional rescue experiments further indicated that COX17 is an important downstream mediator of p53-associated sensitivity to elesclomol. Conditioned media from elesclomol-treated, COX17-overexpressing tumor cells inhibited HUVEC tube formation and proliferation and increased oxidative stress. In xenografts, elesclomol reduced tumor growth, which was further suppressed by COX17 overexpression and partially attenuated by COX17 silencing, accompanied by increased tumor copper accumulation, upregulation of p53/COX17/SLC31A1, and downregulation of ATP7A. These findings suggest that the p53-COX17 axis links copper metabolism to elesclomol-associated antitumor activity in gastric cancer. COX17 may enhance copper accumulation, oxidative stress, tumor-cell-death-associated changes, and angiogenesis-related phenotypic inhibition. Further studies using canonical cuproptosis markers, copper chelator rescue experiments, additional gastric cancer cell lines with different p53 backgrounds, and clinical validation are required to confirm the translational significance of this pathway.

Immunotherapy has shown great potential for treating aggressive cancers and it is becoming the fourth and newest pillar of cancer therapy complementing surgery, cytotoxic therapy, and radiotherapy. In particular, immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have shown extraordinary clinical efficacy in several types of cancer. This is because tumor cells express molecules, such as the Programmed Death Ligand 1 (PD-L1), to prevent immune cells activity (immune-evasion). The immune checkpoint protein Programmed Death receptor 1 (PD-1) expressed by lymphocytes instructs T-cells not to attack any tumor cell expressing PD-L1. Several therapies anti PD-1/PD-L1 have been approved by FDA, but concerns have been raised about their long term efficacy and safety. Therefore, there is a need for better understanding of the biology and the mechanisms regulating PD-1/PD-L1 axis, to develop different approaches to target this pathway. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for increasing the efficacy and reducing side effects of the current anti PD-L1 antibodies. Copper transporter 1 (CTR-1) and copper levels are elevated in tumors and the use of copper targeting agents is currently under intense investigations. It has been also reported that copper plays a major role in the immune-system, but its activity is unclear. In this study we demonstrated that copper plays a key role in the expression of PD-L1 in cancer cells. Tissue microarrays from neuroblastoma (NB) and glioblastoma patients showed a significant correlation between CTR-1 and PD-L1 expression (p=0.00014 and p=0.012 respectively). In vitro experiments showed that downregulation of CTR-1 caused a decrease of intracellular copper which in turn led to a downregulation of PD-L1 expression in cancer cells. On the other hand, addition of copper into the media clearly induced PD-L1 upregulation. RNA-seq analysis revealed specific pathways and candidate genes associated with tumor copper homeostasis and PD-L1 expression. Consistently, Dextran-Catechin (DC) and TEPA, drugs reducing copper, were able to downregulate PD-L1 expression in tumors. In vivo studies showed that copper lowering drugs prolonged mice survival, and ex vivo immunohistochemistry staining confirmed the downregulation of CTR1 and PD-L1 expression. In addition, 24h and 48h of DC treatments showed an increase of tumor-infiltrating CD4+ and CD8+ lymphocytes and activated Natural Killer cells (NK) cells in NB immune-competent mouse model. In conclusion, there is a strong association between PD-L1 expression and intracellular copper levels. Copper dysregulating agents reduce PD-L1 in vitro and in vivo, highlighting the possibility to enhance tumor immune surveillance by targeting intracellular copper levels. This study shows the potential utility of copper targeting drugs to improve anti-cancer immunotherapies. Citation Format: Florida Voli, Luigi Lerra, Kathleen Kimpton, Federica Saletta, Sylvie Shen, Giuseppe Cirillo, Maria Kavallaris, Orazio Vittorio. Copper homeostasis: A new player in anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3224.

Inhibition of CTR1 expression improves hypoxia/reoxygenation-induced myoblast injury by blocking cuproptosis