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HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis.
Schneegans, Svenja; Löptien, Jana; Mojzisch, Angelika; Loreth, Desirée; Kretz, Oliver; Raschdorf, Christoph; Hanssen, Annkathrin; Gocke, Antonia; Siebels, Bente; Gunasekaran, Karthikeyan; Ding, Yi; Oliveira-Ferrer, Leticia; Brylka, Laura; Schinke, Thorsten; Schlüter, Hartmut; Paatero, Ilkka; Voß, Hannah; Werner, Stefan; Pantel, Klaus; Wikman, Harriet.
Afiliación
  • Schneegans S; Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
  • Löptien J; Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
  • Mojzisch A; Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
  • Loreth D; Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
  • Kretz O; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Raschdorf C; Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
  • Hanssen A; Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
  • Gocke A; Section Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Siebels B; Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg- Eppendorf, Hamburg, Germany.
  • Gunasekaran K; Section Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Ding Y; Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Oliveira-Ferrer L; Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Brylka L; Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Schinke T; Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Schlüter H; Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Paatero I; Section Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Voß H; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
  • Werner S; Section Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Pantel K; Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
  • Wikman H; Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
J Exp Clin Cancer Res ; 43(1): 110, 2024 Apr 11.
Article en En | MEDLINE | ID: mdl-38605423
ABSTRACT

BACKGROUND:

Metastasis is the leading cause of cancer-related death in non-small cell lung cancer (NSCLC) patients. We previously showed that low HERC5 expression predicts early tumor dissemination and a dismal prognosis in NSCLC patients. Here, we performed functional studies to unravel the mechanism underlying the "metastasis-suppressor" effect of HERC5, with a focus on mitochondrial metabolism pathways.

METHODS:

We assessed cell proliferation, colony formation potential, anchorage-independent growth, migration, and wound healing in NSCLC cell line models with HERC5 overexpression (OE) or knockout (KO). To study early tumor cell dissemination, we used these cell line models in zebrafish experiments and performed intracardial injections in nude mice. Mass spectrometry (MS) was used to analyze protein changes in whole-cell extracts. Furthermore, electron microscopy (EM) imaging, cellular respiration, glycolytic activity, and lactate production were used to investigate the relationships with mitochondrial energy metabolism pathways.

RESULTS:

Using different in vitro NSCLC cell line models, we showed that NSCLC cells with low HERC5 expression had increased malignant and invasive properties. Furthermore, two different in vivo models in zebrafish and a xenograft mouse model showed increased dissemination and metastasis formation (in particular in the brain). Functional enrichment clustering of MS data revealed an increase in mitochondrial proteins in vitro when HERC5 levels were high. Loss of HERC5 leads to an increased Warburg effect, leading to improved adaptation and survival under prolonged inhibition of oxidative phosphorylation.

CONCLUSIONS:

Taken together, these results indicate that low HERC5 expression increases the metastatic potential of NSCLC in vitro and in vivo. Furthermore, HERC5-induced proteomic changes influence mitochondrial pathways, ultimately leading to alterations in energy metabolism and demonstrating its role as a new potential metastasis suppressor gene.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Pulmón de Células no Pequeñas / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: J Exp Clin Cancer Res Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Pulmón de Células no Pequeñas / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: J Exp Clin Cancer Res Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido