S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation

Masayasu Toyomoto, Asuka Inoue, Kei Iida, Masatsugu Denawa, Isao Kii, Francois Marie Ngako Kadji, Takayuki Kishi, Dohyun Im, Tatsuro Shimamura, Hiroshi Onogi, Suguru Yoshida, So Iwata, Junken Aoki, Takamitsu Hosoya, Masatoshi Hagiwara

Research output: Contribution to journalArticlepeer-review

Abstract

Metabolic activities are altered in cancer cells compared with those in normal cells, and the cancer-specific pathway becomes a potential therapeutic target. Higher cellular glucose consumption, which leads to lower glucose levels, is a hallmark of cancer cells. In an objective screening for chemicals that induce cell death under low-glucose conditions, we discovered a compound, denoted as ALESIA (Anticancer Ligand Enhancing Starvation-induced Apoptosis). By our shedding assay of transforming growth factor α in HEK293A cells, ALESIA was determined to act as a sphingosine-1-phosphate receptor 3–G12-biased agonist that promotes nitric oxide production and oxidative stress. The oxidative stress triggered by ALESIA resulted in the exhaustion of glucose, cellular NADPH deficiency, and then cancer cell death. Intraperitoneal administration of ALESIA improved the survival of mice with peritoneally disseminated rhabdomyosarcoma, indicating its potential as a new type of anticancer drug for glucose starvation therapy. Toyomoto et al. demonstrate that ALESIA is a type of biased agonist targeting the S1PR3–G12 signaling pathway that can induce cancer-specific glucose starvation. This discovery highlights the possible existence of an endogenous biased ligand that modulates signaling in four major families of heterotrimeric G protein.

Original languageEnglish
JournalCell chemical biology
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • GPCR
  • S1PR3
  • biased agonist
  • cancer therapy
  • glucose starvation
  • nitric oxide
  • oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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