Options
MCU controls melanoma progression through a redox‐controlled phenotype switch
ISSN
1469-221X
Date Issued
2022
Author(s)
Stejerean‐Todoran, Ioana
Zimmermann, Katharina
Gibhardt, Christine S
Vultur, Adina
Ickes, Christian
Shannan, Batool
Bonilla del Rio, Zuriñe
Wölling, Anna
Sung, Hsu‐Min
Shumanska, Magdalena
Zhang, Xin
Nanadikar, Maithily
Latif, Muhammad U
Wittek, Anna
Lange, Felix
Waters, Andrea
Brafford, Patricia
Ellenrieder, Volker
Roesch, Alexander
Herlyn, Meenhard
Stanisz, Hedwig
DOI
10.15252/embr.202254746
Abstract
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 MCUA expression correlates with melanoma patient survival and is decreased in BRAF kinase inhibitor‐resistant melanomas. Knockdown (KD) of MCUA suppresses melanoma cell growth and stimulates migration and invasion. In melanoma xenografts, MCUA_KD reduces tumor volumes but promotes lung metastases. Proteomic analyses and protein microarrays identify pathways that link MCUA and melanoma cell phenotype and suggest a major role for redox regulation. Antioxidants enhance melanoma cell migration, while prooxidants diminish the MCUA_KD‐induced invasive phenotype. Furthermore, MCUA_KD increases melanoma cell resistance to immunotherapies and ferroptosis. Collectively, we demonstrate that MCUA 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.
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 MCUA expression correlates with melanoma patient survival and is decreased in BRAF kinase inhibitor‐resistant melanomas. Knockdown (KD) of MCUA suppresses melanoma cell growth and stimulates migration and invasion. In melanoma xenografts, MCUA_KD reduces tumor volumes but promotes lung metastases. Proteomic analyses and protein microarrays identify pathways that link MCUA and melanoma cell phenotype and suggest a major role for redox regulation. Antioxidants enhance melanoma cell migration, while prooxidants diminish the MCUA_KD‐induced invasive phenotype. Furthermore, MCUA_KD increases melanoma cell resistance to immunotherapies and ferroptosis. Collectively, we demonstrate that MCUA 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.
Synopsis
image
The MCU channel complex is the main route for Ca2+ into the mitochondrial matrix. MCU controls cellular redox state, disease aggressiveness and therapeutic response and is a favorable prognostic marker in melanoma.
MCU controls mitochondrial Ca2+ dynamics, production of ROS and ATP in melanoma cells.
MCU downregulation hinders melanoma cell growth and stimulates cellular motility and metastasis.
Melanoma cells develop increased resistance to immunotherapies and ferroptosis inducers upon MCU downregulation.
image
The MCU channel complex is the main route for Ca2+ into the mitochondrial matrix. MCU controls cellular redox state, disease aggressiveness and therapeutic response and is a favorable prognostic marker in melanoma.
MCU controls mitochondrial Ca2+ dynamics, production of ROS and ATP in melanoma cells.
MCU downregulation hinders melanoma cell growth and stimulates cellular motility and metastasis.
Melanoma cells develop increased resistance to immunotherapies and ferroptosis inducers upon MCU downregulation.
The MCU channel complex is the main route for Ca2+ into the mitochondrial matrix. MCU controls cellular redox state, disease aggressiveness and therapeutic response and is a favorable prognostic marker in melanoma.
image
image
File(s)
No Thumbnail Available
Name
EMBR_EMBR202254746.pdf
Size
5.08 MB
Checksum (MD5)
118cdc4617b162909e9b55b33fc79fc2
