Anti-tumor effects and potential therapeutic response biomarkers in α-emitting meta-211At-astato-benzylguanidine therapy for malignant pheochromocytoma explored by RNA-sequencing

Yasuhiro Ohshima, Nobuaki Kono, Yuichiro Yokota, Shigeki Watanabe, Ichiro Sasaki, Noriko S. Ishioka, Tetsuya Sakashita, Kazuharu Arakawa

Research output: Contribution to journalArticle

Abstract

Targeted α-particle therapy is a promising option for patients with malignant pheochromocytoma. Recent observations regarding meta-211At-astato-benzylguanidine (211At-MABG) in a pheochromocytoma mouse model showed a strong anti-tumor effect, though the molecular mechanism remains elusive. Here, we present the first comprehensive RNA-sequencing (RNA-seq) data for pheochromocytoma cells based on in vitro 211At-MABG administration experiments. Key genes and pathways in the tumor α-particle radiation response are also examined to obtain potential response biomarkers. Methods: We evaluated genome-wide transcriptional alterations in the rat pheochromocytoma cell line PC12 at 3, 6, and 12 h after 211At-MABG treatment; a control experiment using 60Co γ-ray irradiation was carried out to highlight 211At-MABG-specific gene expression. For comparisons, 10% and 80% iso-survival doses (0.8 and 0.1 kBq/mL for 211At-MABG and 10 and 1 Gy for 60Co γ-rays) were used. Results: Enrichment analysis of differentially expressed genes (DEGs) and analysis of the gene expression profiles of cell cycle checkpoints revealed similar modes of cell death via the p53-p21 signaling pathway after 211At-MABG treatment and γ-ray irradiation. The top list of ranked DEGs demonstrated the expression of key genes on the decrease in the survival following 211At-MABG exposure, and four potential genes (Mien1, Otub1, Vdac1 and Vegfa genes) of 211At-MABG therapy. Western blot analysis indicated increased expression of TSPO in 211At-MABG-treated cells, suggesting its potential as a PET imaging probe. Conclusion: Comprehensive RNA-seq revealed contrasting cellular responses to γ-ray and α-particle therapy, leading to the identification of four potential candidate genes that may serve as molecular imaging and 211At-MABG therapy targets.

Original languageEnglish
Pages (from-to)1538-1549
Number of pages12
JournalTheranostics
Volume9
Issue number6
DOIs
Publication statusPublished - 2019 Jan 1

Keywords

  • Meta-At-astato-benzylguanidine
  • PET imaging
  • Pheochromocytoma
  • RNA-sequencing
  • Radionuclide therapy
  • α-particle

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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