Anti-tumor effects and potential therapeutic response biomarkers in α-emitting meta- 211 At-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 vitro211At-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

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RNA Sequence Analysis
Pheochromocytoma
Therapeutic Uses
Biomarkers
Neoplasms
Genes
Therapeutics
RNA
Gene Expression
benzylguanidine
1-(3-astatobenzyl)guanidine
Molecular Imaging
Survival
PC12 Cells
Cell Cycle Checkpoints
Transcriptome
Cell Death
Western Blotting
Genome
Radiation

Keywords

  • meta-211At-astato-benzylguanidine
  • PET imaging
  • pheochromocytoma
  • radionuclide therapy
  • RNA-sequencing
  • α-particle

ASJC Scopus subject areas

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

Cite this

Anti-tumor effects and potential therapeutic response biomarkers in α-emitting meta- 211 At-astato-benzylguanidine therapy for malignant pheochromocytoma explored by RNA-sequencing . / Ohshima, Yasuhiro; Kono, Nobuaki; Yokota, Yuichiro; Watanabe, Shigeki; Sasaki, Ichiro; Ishioka, Noriko S.; Sakashita, Tetsuya; Arakawa, Kazuharu.

In: Theranostics, Vol. 9, No. 6, 01.01.2019, p. 1538-1549.

Research output: Contribution to journalArticle

Ohshima, Yasuhiro ; Kono, Nobuaki ; Yokota, Yuichiro ; Watanabe, Shigeki ; Sasaki, Ichiro ; Ishioka, Noriko S. ; Sakashita, Tetsuya ; Arakawa, Kazuharu. / Anti-tumor effects and potential therapeutic response biomarkers in α-emitting meta- 211 At-astato-benzylguanidine therapy for malignant pheochromocytoma explored by RNA-sequencing In: Theranostics. 2019 ; Vol. 9, No. 6. pp. 1538-1549.
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title = "Anti-tumor effects and potential therapeutic response biomarkers in α-emitting meta- 211 At-astato-benzylguanidine therapy for malignant pheochromocytoma explored by RNA-sequencing",
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 vitro211At-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.",
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author = "Yasuhiro Ohshima and Nobuaki Kono and Yuichiro Yokota and Shigeki Watanabe and Ichiro Sasaki and Ishioka, {Noriko S.} and Tetsuya Sakashita and Kazuharu Arakawa",
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AU - Yokota, Yuichiro

AU - Watanabe, Shigeki

AU - Sasaki, Ichiro

AU - Ishioka, Noriko S.

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N2 - 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 vitro211At-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.

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