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Caveolin-1 mediates the utilization of extracellular proteins for survival in refractory gastric cancer.

Nahee HwangBo Kyung YoonKyu-Hye ChunHyeonhui KimYoseob LeeJae-Won KimHyeonuk JeonTae-Hyun KimMi Young KimSungSoon FangJae Ho CheongJae-Woo Kim
Published in: Experimental & molecular medicine (2023)
Despite advances in cancer therapy, the clinical outcome of patients with gastric cancer remains poor, largely due to tumor heterogeneity. Thus, finding a hidden vulnerability of clinically refractory subtypes of gastric cancer is crucial. Here, we report that chemoresistant gastric cancer cells rely heavily on endocytosis, facilitated by caveolin-1, for survival. caveolin-1 was highly upregulated in the most malignant stem-like/EMT/mesenchymal (SEM)-type gastric cancer cells, allowing caveolin-1-mediated endocytosis and utilization of extracellular proteins via lysosomal degradation. Downregulation of caveolin-1 alone was sufficient to induce cell death in SEM-type gastric cancer cells, emphasizing its importance as a survival mechanism. Consistently, chloroquine, a lysosomal inhibitor, successfully blocked caveolin-1-mediated endocytosis, leading to the marked suppression of tumor growth in chemorefractory gastric cancer cells in vitro, including patient-derived organoids, and in vivo. Together, our findings suggest that caveolin-1-mediated endocytosis is a key metabolic pathway for gastric cancer survival and a potential therapeutic target.
Keyphrases
  • cell death
  • cancer therapy
  • stem cells
  • epithelial mesenchymal transition
  • climate change
  • signaling pathway
  • single cell
  • plasmodium falciparum