Open Access

Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis

  • Authors:
    • Weifan Lin
    • Xiangwan Lu
    • Hang Yang
    • Linxuan Huang
    • Wuheng Huang
    • Yuluan Tang
    • Situn Liu
    • Hua Wang
    • Yan Zhang
  • View Affiliations

  • Published online on: August 16, 2022     https://doi.org/10.3892/ijmm.2022.5180
  • Article Number: 124
  • Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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 ferrop-tosis 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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October-2022
Volume 50 Issue 4

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Copy and paste a formatted citation
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Spandidos Publications style
Lin W, Lu X, Yang H, Huang L, Huang W, Tang Y, Liu S, Wang H and Zhang Y: Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis. Int J Mol Med 50: 124, 2022
APA
Lin, W., Lu, X., Yang, H., Huang, L., Huang, W., Tang, Y. ... Zhang, Y. (2022). Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis. International Journal of Molecular Medicine, 50, 124. https://doi.org/10.3892/ijmm.2022.5180
MLA
Lin, W., Lu, X., Yang, H., Huang, L., Huang, W., Tang, Y., Liu, S., Wang, H., Zhang, Y."Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis". International Journal of Molecular Medicine 50.4 (2022): 124.
Chicago
Lin, W., Lu, X., Yang, H., Huang, L., Huang, W., Tang, Y., Liu, S., Wang, H., Zhang, Y."Metabolic heterogeneity protects metastatic mucosal melanomas cells from ferroptosis". International Journal of Molecular Medicine 50, no. 4 (2022): 124. https://doi.org/10.3892/ijmm.2022.5180