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MCU controls melanoma progression through a redox-controlled phenotype switch.

ABSTRACT: Melanoma is the deadliest of skin cancers and has a high tendency to metastasize to distant organs. Calcium and metabolic signals contribute to melanoma invasiveness; however, the underlying molecular details are elusive. The MCU complex is a major route for calcium into the mitochondrial matrix but whether MCU affects melanoma pathobiology was not understood. Here, we show that MCU_A expression correlates with melanoma patient survival and is decreased in BRAF kinase inhibitor-resistant melanomas. Knockdown (KD) of MCU_A suppresses melanoma cell growth and stimulates migration and invasion. In melanoma xenografts, MCU_{A_KD} reduces tumor volumes but promotes lung metastases. Proteomic analyses and protein microarrays identify pathways that link MCU_A and melanoma cell phenotype and suggest a major role for redox regulation. Antioxidants enhance melanoma cell migration, while prooxidants diminish the MCU_{A_KD} -induced invasive phenotype. Furthermore, MCU_{A_KD} increases melanoma cell resistance to immunotherapies and ferroptosis. Collectively, we demonstrate that MCU_A controls melanoma aggressive behavior and therapeutic sensitivity. Manipulations of mitochondrial calcium and redox homeostasis, in combination with current therapies, should be considered in treating advanced melanoma.

SUBMITTER: Stejerean-Todoran I

PROVIDER: S-EPMC9638851 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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MCU controls melanoma progression through a redox-controlled phenotype switch.

Stejerean-Todoran Ioana I Zimmermann Katharina K Gibhardt Christine S CS Vultur Adina A Ickes Christian C Shannan Batool B Bonilla Del Rio Zuriñe Z Wölling Anna A Cappello Sabrina S Sung Hsu-Min HM Shumanska Magdalena M Zhang Xin X Nanadikar Maithily M Latif Muhammad U MU Wittek Anna A Lange Felix F Waters Andrea A Brafford Patricia P Wilting Jörg J Urlaub Henning H Katschinski Dörthe M DM Rehling Peter P Lenz Christof C Jakobs Stefan S Ellenrieder Volker V Roesch Alexander A Schön Michael P MP Herlyn Meenhard M Stanisz Hedwig H Bogeski Ivan I

EMBO reports 20220926 11

Melanoma is the deadliest of skin cancers and has a high tendency to metastasize to distant organs. Calcium and metabolic signals contribute to melanoma invasiveness; however, the underlying molecular details are elusive. The MCU complex is a major route for calcium into the mitochondrial matrix but whether MCU affects melanoma pathobiology was not understood. Here, we show that MCU<sub>A</sub> expression correlates with melanoma patient survival and is decreased in BRAF kinase inhibitor-resista ...[more]

PMID: 36156348

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Project description:Melanoma is the most aggressive type of skin cancer. Despite the available therapies, the minimum residual disease is still refractory. Reactive oxygen and nitrogen species (ROS and RNS) play a dual role in melanoma, where redox imbalance is involved from initiation to metastasis and resistance. Redox proteins modulate the disease by controlling ROS/RNS levels in immune response, proliferation, invasion, and relapse. Chemotherapeutics such as BRAF and MEK inhibitors promote oxidative stress, but high ROS/RNS amounts with a robust antioxidant system allow cells to be adaptive and cooperate to non-toxic levels. These proteins could act as biomarkers and possible targets. By understanding the complex mechanisms involved in adaptation and searching for new targets to make cells more susceptible to treatment, the disease might be overcome. Therefore, exploring the role of redox-sensitive proteins and the modulation of redox homeostasis may provide clues to new therapies. This study analyzes information obtained from a public cohort of melanoma patients about the expression of redox-generating and detoxifying proteins in melanoma during the disease stages, genetic alterations, and overall patient survival status. According to our analysis, 66% of the isoforms presented differential expression on melanoma progression: NOS2, SOD1, NOX4, PRX3, PXDN and GPX1 are increased during melanoma progression, while CAT, GPX3, TXNIP, and PRX2 are decreased. Besides, the stage of the disease could influence the result as well. The levels of PRX1, PRX5 and PRX6 can be increased or decreased depending on the stage. We showed that all analyzed isoforms presented some genetic alteration on the gene, most of them (78%) for increased mRNA expression. Interestingly, 34% of all melanoma patients showed genetic alterations on TRX1, most for decreased mRNA expression. Additionally, 15% of the isoforms showed a significant reduction in overall patient survival status for an altered group (PRX3, PRX5, TR2, and GR) and the unaltered group (NOX4). Although no such specific antioxidant therapy is approved for melanoma yet, inhibitors or mimetics of these redox-sensitive proteins have achieved very promising results. We foresee that forthcoming investigations on the modulation of these proteins will bring significant advances for cancer therapy.

Dataset Information

MCU controls melanoma progression through a redox-controlled phenotype switch.

Publications

MCU controls melanoma progression through a redox-controlled phenotype switch.

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