HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis
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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.
In: J EXP CLIN CANC RES, Vol. 43, No. 1, 11.04.2024, p. 110.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis
AU - Schneegans, Svenja
AU - Löptien, Jana
AU - Mojzisch, Angelika
AU - Loreth, Desirée
AU - Kretz, Oliver
AU - Raschdorf, Christoph
AU - Hanssen, Annkathrin
AU - Gocke, Antonia
AU - Siebels, Bente
AU - Gunasekaran, Karthikeyan
AU - Ding, Yi
AU - Oliveira-Ferrer, Leticia
AU - Brylka, Laura
AU - Schinke, Thorsten
AU - Schlüter, Hartmut
AU - Paatero, Ilkka
AU - Voß, Hannah
AU - Werner, Stefan
AU - Pantel, Klaus
AU - Wikman, Harriet
N1 - © 2024. The Author(s).
PY - 2024/4/11
Y1 - 2024/4/11
N2 - 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.
AB - 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.
U2 - 10.1186/s13046-024-03020-z
DO - 10.1186/s13046-024-03020-z
M3 - SCORING: Journal article
C2 - 38605423
VL - 43
SP - 110
JO - J EXP CLIN CANC RES
JF - J EXP CLIN CANC RES
SN - 1756-9966
IS - 1
ER -