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Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis

Cancer heterogeneity has been proposed to be one of the main causes of metastatic dissemination and therapy failure. However, the underlying mechanisms of this phenomenon remain poorly understood. Melanoma is an aggressive malignancy with a high heterogeneity and metastatic potential. Therefore, the...

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Autores principales: Lin, Weifan, Lu, Xiangwan, Yang, Hang, Huang, Linxuan, Huang, Wuheng, Tang, Yuluan, Liu, Situn, Wang, Hua, Zhang, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9448297/
https://www.ncbi.nlm.nih.gov/pubmed/36004461
http://dx.doi.org/10.3892/ijmm.2022.5180
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author Lin, Weifan
Lu, Xiangwan
Yang, Hang
Huang, Linxuan
Huang, Wuheng
Tang, Yuluan
Liu, Situn
Wang, Hua
Zhang, Yan
author_facet Lin, Weifan
Lu, Xiangwan
Yang, Hang
Huang, Linxuan
Huang, Wuheng
Tang, Yuluan
Liu, Situn
Wang, Hua
Zhang, Yan
author_sort Lin, Weifan
collection PubMed
description Cancer heterogeneity has been proposed to be one of the main causes of metastatic dissemination and therapy failure. However, the underlying mechanisms of this phenomenon remain poorly understood. Melanoma is an aggressive malignancy with a high heterogeneity and metastatic potential. Therefore, the present study investigated the possible association between cancer heterogeneity and metastasis in melanoma. In total, two novel Chinese oral mucosal melanoma (COMM) cell lines, namely COMM-1 and COMM-2, were established for exploring methods into preventing the loss of cellular heterogeneity caused by long-term cell culture. Each cell line was grown under two different models of culture, which yielded two subtypes, one exhibited an adhesive morphology (COMM-AD), whereas the other was grown in suspension (COMM-SUS). Compared with the COMM-AD cells, the COMM-SUS cells exhibited higher metastatic capacities and autofluorescence. Further investigations indicated that the COMM-SUS cells exhibited metabolic reprogramming by taking up lactate produced by COMM-AD cells at increased levels to accumulate NADH through monocarboxylate transporter 1, whilst also increasing NADPH levels through the pentose phosphate pathway (PPP). Additionally, increased NADH and NADPH levels in the COMM-SUS cells, coupled with the upregulation of the anti-ferroptotic proteins, glutathione peroxidase 4 and ferroptosis suppressor protein 1, enabled them to resist ferroptotic cell death induced by oxidative stress during hematogenous dissemination. The inhibition of ferroptosis was found to substantially increase the metastatic capacity of COMM-AD cells. Furthermore, suppressing lactate uptake and impairing PPP activation significantly decreased the metastatic potential of the COMM-SUS cells. Thus, the present study on metabolic heterogeneity in COMM cells potentially provides a novel perspective for exploring this mechanism underlying cancer metastasis.
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spelling pubmed-94482972022-09-19 Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis Lin, Weifan Lu, Xiangwan Yang, Hang Huang, Linxuan Huang, Wuheng Tang, Yuluan Liu, Situn Wang, Hua Zhang, Yan Int J Mol Med Articles Cancer heterogeneity has been proposed to be one of the main causes of metastatic dissemination and therapy failure. However, the underlying mechanisms of this phenomenon remain poorly understood. Melanoma is an aggressive malignancy with a high heterogeneity and metastatic potential. Therefore, the present study investigated the possible association between cancer heterogeneity and metastasis in melanoma. In total, two novel Chinese oral mucosal melanoma (COMM) cell lines, namely COMM-1 and COMM-2, were established for exploring methods into preventing the loss of cellular heterogeneity caused by long-term cell culture. Each cell line was grown under two different models of culture, which yielded two subtypes, one exhibited an adhesive morphology (COMM-AD), whereas the other was grown in suspension (COMM-SUS). Compared with the COMM-AD cells, the COMM-SUS cells exhibited higher metastatic capacities and autofluorescence. Further investigations indicated that the COMM-SUS cells exhibited metabolic reprogramming by taking up lactate produced by COMM-AD cells at increased levels to accumulate NADH through monocarboxylate transporter 1, whilst also increasing NADPH levels through the pentose phosphate pathway (PPP). Additionally, increased NADH and NADPH levels in the COMM-SUS cells, coupled with the upregulation of the anti-ferroptotic proteins, glutathione peroxidase 4 and ferroptosis suppressor protein 1, enabled them to resist ferroptotic cell death induced by oxidative stress during hematogenous dissemination. The inhibition of ferroptosis was found to substantially increase the metastatic capacity of COMM-AD cells. Furthermore, suppressing lactate uptake and impairing PPP activation significantly decreased the metastatic potential of the COMM-SUS cells. Thus, the present study on metabolic heterogeneity in COMM cells potentially provides a novel perspective for exploring this mechanism underlying cancer metastasis. D.A. Spandidos 2022-08-16 /pmc/articles/PMC9448297/ /pubmed/36004461 http://dx.doi.org/10.3892/ijmm.2022.5180 Text en Copyright: © Lin et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Lin, Weifan
Lu, Xiangwan
Yang, Hang
Huang, Linxuan
Huang, Wuheng
Tang, Yuluan
Liu, Situn
Wang, Hua
Zhang, Yan
Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis
title Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis
title_full Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis
title_fullStr Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis
title_full_unstemmed Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis
title_short Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis
title_sort metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9448297/
https://www.ncbi.nlm.nih.gov/pubmed/36004461
http://dx.doi.org/10.3892/ijmm.2022.5180
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