G-protein signaling of oxytocin receptor as a potential target for cabazitaxel-resistant prostate cancer

Hiroshi Hongo, Takeo Kosaka, Ken Ichi Takayama, Yuto Baba, Yota Yasumizu, Koji Ueda, Yutaka Suzuki, Satoshi Inoue, Himisha Beltran, Mototsugu Oya

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Although the treatment armamentarium for patients with metastatic prostate cancer has improved recently, treatment options after progression on cabazitaxel (CBZ) are limited. To identify the mechanisms underlying CBZ resistance and therapeutic targets, we performed single-cell RNA sequencing of circulating tumor cells (CTCs) from patients with CBZ-resistant prostate cancer. Cells were clustered based on gene expression profiles. In silico screening was used to nominate candidate drugs for overcoming CBZ resistance in castration-resistant prostate cancer. CTCs were divided into three to four clusters, reflecting intrapatient tumor heterogeneity in refractory prostate cancer. Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. Cloperastine (CLO) had significant antitumor activity against CBZ-resistant prostate cancer cells. Mass spectrometric phosphoproteome analysis revealed the suppression of OXT signaling specific to CBZ-resistant models. These results support the potential of CLO as a candidate drug for overcoming CBZ-resistant prostate cancer via the inhibition of OXT signaling.

Original languageEnglish
Article numberpgae002
JournalPNAS Nexus
Volume3
Issue number1
DOIs
Publication statusPublished - 2024 Jan 1

Keywords

  • G-protein signaling
  • cabazitaxel-resistant prostate cancer
  • oxytocin

ASJC Scopus subject areas

  • General

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