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<p>Carbonic anhydrase IX (CA-IX) is a transmembrane enzyme overexpressed in melanoma cells, contributing to tumor progression by promoting extracellular acidification. This acidic environment facilitates tumor growth and metastasis. In this study, we investigated the effects of pharmacological CA-IX inhibition on melanoma cell behavior, focusing on the MAPK signaling pathway in A375 cells harboring a BRAF mutation. Acetazolamide (AAZ), a well-known CA-IX inhibitor, was used to evaluate these effects. Treatment with AAZ resulted in a noticeable increase in extracellular pH, alongside a significant reduction in cell viability, suggesting impaired cell survival. Furthermore, AAZ treatment led to decreased phosphorylation of B-Raf and ERK proteins, indicating suppression of MAPK signaling activity. In addition to assessing <i>CA9</i>, which served as the primary target throughout this study, we also analyzed the expression of the hypoxia-related gene <i>HIF1A</i> to further support our findings. The observed changes suggest that CA-IX inhibition also disrupts the cellular adaptation to hypoxic conditions. Overall, our findings demonstrate a functional relationship between CA-IX activity, extracellular pH regulation, and oncogenic signaling in melanoma cells. These results support the therapeutic potential of CA-IX inhibition in targeting BRAF-mutant melanoma and provide valuable insights for future in vivo studies and potential clinical applications.</p>

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Targeting Carbonic Anhydrase IX Suppresses MAPK Activity and Viability in BRAF-Mutant Melanoma

  • 期刊论文

  • 发表日期：

    2025年7月31日

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  • Beyza Ecem Oz-Bedir,
  • Ozen Ozensoy Guler

摘要

Carbonic anhydrase IX (CA-IX) is a transmembrane enzyme overexpressed in melanoma cells, contributing to tumor progression by promoting extracellular acidification. This acidic environment facilitates tumor growth and metastasis. In this study, we investigated the effects of pharmacological CA-IX inhibition on melanoma cell behavior, focusing on the MAPK signaling pathway in A375 cells harboring a BRAF mutation. Acetazolamide (AAZ), a well-known CA-IX inhibitor, was used to evaluate these effects. Treatment with AAZ resulted in a noticeable increase in extracellular pH, alongside a significant reduction in cell viability, suggesting impaired cell survival. Furthermore, AAZ treatment led to decreased phosphorylation of B-Raf and ERK proteins, indicating suppression of MAPK signaling activity. In addition to assessing CA9, which served as the primary target throughout this study, we also analyzed the expression of the hypoxia-related gene HIF1A to further support our findings. The observed changes suggest that CA-IX inhibition also disrupts the cellular adaptation to hypoxic conditions. Overall, our findings demonstrate a functional relationship between CA-IX activity, extracellular pH regulation, and oncogenic signaling in melanoma cells. These results support the therapeutic potential of CA-IX inhibition in targeting BRAF-mutant melanoma and provide valuable insights for future in vivo studies and potential clinical applications.