Betulinic acid-mediated tuning of PERK/CHOP signaling by sp1 inhibition as a novel therapeutic strategy for glioblastoma

Wei Lun Lo, Tsung I. Hsu, Wen Bin Yang, Tzu Jen Kao, Ming Hsiao Wu, Yung Ning Huang, Shiu Hwa Yeh, Jian Ying Chuang

研究成果: 雜誌貢獻文章

摘要

Patients with glioblastoma are at high risk of local recurrences after initial treatment with standard therapy, and recurrent tumor cells appear to be resistant to first-line drug temozolomide. Thus, finding an effective second-line agent for treating primary and recurrent glioblastomas is critical. Betulinic acid (BA), a natural product of plant origin, can cross the blood–brain barrier. Here, we investigated the antitumor effects of BA on typical glioblastoma cell lines and primary glioblastoma cells from patients, as well as corresponding temozolomide-resistant cells. Our findings verified that BA significantly reduced growth in all examined cells. Furthermore, gene-expression array analysis showed that the unfolded-protein response was significantly affected by BA. Moreover, BA treatment increased activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptotic pathway, and reduced specificity protein 1 (Sp1) expression. However, Sp1 overexpression reversed the observed cell-growth inhibition and PERK/CHOP signaling activation induced by BA. Because temozolomide-resistant cells exhibited significantly increased Sp1 expression, we concluded that Sp1-mediated PERK/CHOP signaling inhibition protects glioblastoma against cancer therapies; hence, BA treatment targeting this pathway can be considered as an effective therapeutic strategy to overcome such chemoresistance and tumor relapse.
原文英語
文章編號981
期刊Cancers
12
發行號4
DOIs
出版狀態已發佈 - 四月 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

指紋 深入研究「Betulinic acid-mediated tuning of PERK/CHOP signaling by sp1 inhibition as a novel therapeutic strategy for glioblastoma」主題。共同形成了獨特的指紋。

  • 引用此