Stellettin B Sensitizes Glioblastoma to DNA-Damaging Treatments by Suppressing PI3K-Mediated Homologous Recombination Repair

Xin Peng, Shaolu Zhang, Yingying Wang, Zhicheng Zhou, Zixiang Yu, Zhenxing Zhong, Liang Zhang, Zhe Sheng Chen, Francois X. Claret, Moshe Elkabets, Feng Wang, Fan Sun, Ran Wang, Han Liang, Hou Wen Lin, Dexin Kong

Research output: Contribution to journalArticlepeer-review

Abstract

Glioblastoma (GBM) is the most aggressive type of cancer. Its current first-line postsurgery regimens are radiotherapy and temozolomide (TMZ) chemotherapy, both of which are DNA damage-inducing therapies but show very limited efficacy and a high risk of resistance. There is an urgent need to develop novel agents to sensitize GBM to DNA-damaging treatments. Here it is found that the triterpene compound stellettin B (STELB) greatly enhances the sensitivity of GBM to ionizing radiation and TMZ in vitro and in vivo. Mechanistically, STELB inhibits the expression of homologous recombination repair (HR) factors BRCA1/2 and RAD51 by promoting the degradation of PI3Kα through the ubiquitin-proteasome pathway; and the induced HR deficiency then leads to augmented DNA damage and cell death. It is further demonstrated that STELB has the potential to rapidly penetrate the blood-brain barrier to exert anti-GBM effects in the brain, based on zebrafish and nude mouse orthotopic xenograft tumor models. The study provides strong evidence that STELB represents a promising drug candidate to improve GBM therapy in combination with DNA-damaging treatments.

Original languageEnglish
JournalAdvanced Science
DOIs
StateAccepted/In press - 1 Jan 2022

Keywords

  • DNA-damaging treatment
  • glioblastoma
  • homologous recombination repair
  • PI3K
  • stellettin B

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Chemical Engineering (all)
  • Materials Science (all)
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Engineering (all)
  • Physics and Astronomy (all)

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