Pegylated Recombinant Human Arginase 1 Induces Autophagy and Apoptosis via the ROS-Activated AKT/mTOR Pathway in Bladder Cancer Cells

Oxid Med Cell Longev. 2021 Mar 18:2021:5510663. doi: 10.1155/2021/5510663. eCollection 2021.

Abstract

Bladder cancer is one of the most commonly diagnosed cancers worldwide, especially in males. Current therapeutic interventions, including surgery, radiation therapy, chemotherapy, and immunotherapy, have not been able to improve the clinical outcome of bladder cancer patients with satisfaction. Recombinant human arginase (rhArg, BCT-100) is a novel agent with great anticancer effects on arginine-auxotrophic tumors. However, the effects of BCT-100 on bladder cancer remain unclear. In this study, the in vitro anticancer effects of BCT-100 were assessed using four bladder cancer cell lines (J82, SCaBER, T24, and 5637), while the in vivo effects were evaluated by establishing T24 nude mice xenograft models. Intracellular arginine level was observed to be sharply decreased followed by the onset of apoptotic events. Furthermore, BCT-100 was found to induce H2O2 production and mitochondrial membrane depolarization, leading to the release of mitochondrial cytochrome c and Smac to the cytosol. Treatment with BCT was observed to upregulate the expression of LC3B and Becllin-1, but downregulate the expression of p62 in a time-dependent manner. Autophagic flux was also observed upon BCT-100 treatment. Besides, the phosphorylation of the AKT/mTOR pathway was suppressed in a time-dependent fashion in BCT-100-treated T24 cells. While N-acetyl-L-cysteine was shown to alleviate BCT-100-induced apoptosis and autophagy, chloroquine, MK-2206, and rapamycin were found to potentiate BCT-100-triggered apoptosis. Finally, BCT-100 was demonstrated to induce autophagy and apoptosis via the ROS-mediated AKT/mTOR signaling pathway in bladder cancer cells.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Arginase / pharmacology*
  • Arginine / metabolism
  • Autophagy / drug effects*
  • Cell Line, Tumor
  • Female
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Neoplasm Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Recombinant Proteins / pharmacology*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / metabolism*
  • Urinary Bladder Neoplasms / enzymology
  • Urinary Bladder Neoplasms / pathology*
  • Xenograft Model Antitumor Assays

Substances

  • BCT-100
  • Neoplasm Proteins
  • Reactive Oxygen Species
  • Recombinant Proteins
  • Arginine
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Arginase