The regulators of peroxisomal acyl-carnitine shuttle CROT and CRAT promote metastasis in melanoma
Fecha
2023Autor
Versión
Acceso abierto / Sarbide irekia
Tipo
Artículo / Artikulua
Versión
Versión publicada / Argitaratu den bertsioa
Identificador del proyecto
MINECO//PI16-01911/ES/
ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PI19%2F00645/ES/
AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-116344RB-I00/ES/
MINECO//AF2015-71606R/ES/
AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094507-B-I00/ES/
Gobierno de Navarra//71%2F17
Impacto
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10.1016/j.jid.2022.08.038
Resumen
Circulating tumor cells are the key link between a primary tumor and distant metastases, but once in the
bloodstream, loss of adhesion induces cell death. To identify the mechanisms relevant for melanoma circulating
tumor cell survival, we performed RNA sequencing and discovered that detached melanoma cells and isolated
melanoma circulating tumor cells rewire lipid metabolism by upregulating f ...
[++]
Circulating tumor cells are the key link between a primary tumor and distant metastases, but once in the
bloodstream, loss of adhesion induces cell death. To identify the mechanisms relevant for melanoma circulating
tumor cell survival, we performed RNA sequencing and discovered that detached melanoma cells and isolated
melanoma circulating tumor cells rewire lipid metabolism by upregulating fatty acid (FA) transport and FA betaoxidation‒related genes. In patients with melanoma, high expression of FA transporters and FA beta-oxidation
enzymes significantly correlates with reduced progression-free and overall survival. Among the highest
expressed regulators in melanoma circulating tumor cells were the carnitine transferases carnitine O-octanoyltransferase and carnitine acetyltransferase, which control the shuttle of peroxisome-derived medium-chain FAs
toward mitochondria to fuel mitochondrial FA beta-oxidation. Knockdown of carnitine O-octanoyltransferase or
carnitine acetyltransferase and short-term treatment with peroxisomal or mitochondrial FA beta-oxidation inhibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. Carnitine O-octanoyltransferase
and carnitine acetyltransferase depletion could be rescued by medium-chain FA supplementation, indicating that
the peroxisomal supply of FAs is crucial for the survival of nonadherent melanoma cells. Our study identifies
targeting the FA-based cross-talk between peroxisomes and mitochondria as a potential therapeutic opportunity
to challenge melanoma progression. Moreover, the discovery of the antimetastatic activity of the Food and Drug
Administration‒approved drug ranolazine carries translational potential. [--]
Materias
Circulating tumor cells,
Cell death,
Melanoma metastasis,
Lipid metabolism,
FA transporters,
Carnitine transferases,
Thioridazine,
Ranolazine,
Antimetastatic activity
Editor
Elsevier
Publicado en
Journal of Investigative Dermatology, (2023) 143(2), 305-316
Departamento
Universidad Pública de Navarra. Departamento de Ciencias /
Nafarroako Unibertsitate Publikoa. Zientziak Saila /
Universidad Pública de Navarra. Departamento de Ciencias de la Salud /
Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila
Versión del editor
Entidades Financiadoras
This work was funded by the Instituto de Salud Carlos III-FEDER through PI16-01911 and PI19/00645 to IA. IA and IML acknowledge support through Miguel Servet II fellowships (CPII20/00011 and CPII20/00029). The Health Department of the Government of Navarra, Spain funded work through reference GºNa 71/17. SV is funded by FEDER/Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigación (PID2020-116344-RB-100) and by Foundation Spanish Association Against Cancer (PROYE20029VICE). ILO is funded through a Navarrabiomed PhD studentship and the Grupo Español Multidisciplinar de Melanoma (reference Beca_GEM). FL was funded by the Cancer Research Thematic Network of the Instituto de Salud Carlos III (RTICC RD12/0036/0066, SAF2015-71606R, RTI2018-094507-B-100) financed by MCIN/AEI/10.13039/501100011033 and by FEDER. FL was also funded by the la Caixa Foundation, Caja Navarra Foundation, and the Foundation AECC. PA is a recipient of a Sara Borrell postdoctoral fellowship from the Instituto de Salud Carlos III (CD21/00137).