ATM- and ATR-induced primary ciliogenesis promotes cisplatin resistance in pancreatic ductal adenocarcinoma

Yu Ying Chao, Bu Miin Huang, I. Chen Peng, Pei Rong Lee, Yi Shyun Lai, Wen Tai Chiu, Yi Syuan Lin, Shih Chieh Lin, Jung Hsuan Chang, Pai Sheng Chen, Shaw Jenq Tsai, Chia Yih Wang

研究成果: Article同行評審

摘要

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of its late diagnosis and chemoresistance. Primary cilia, the cellular antennae, are observed in most human cells to maintain development and differentiation. Primary cilia are gradually lost during the progression of pancreatic cancer and are eventually absent in PDAC. Here, we showed that cisplatin-resistant PDAC regrew primary cilia. Additionally, genetic or pharmacological disruption of primary cilia sensitized PDAC to cisplatin treatment. Mechanistically, ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR), tumor suppressors that initiate DNA damage responses, promoted the excessive formation of centriolar satellites (EFoCS) and autophagy activation. Disruption of EFoCS and autophagy inhibited primary ciliogenesis, sensitizing PDAC cells to cisplatin treatment. Collectively, our findings revealed an unexpected interplay among the DNA damage response, primary cilia, and chemoresistance in PDAC and deciphered the molecular mechanism by which ATM/ATR-mediated EFoCS and autophagy cooperatively regulate primary ciliogenesis.

原文English
頁(從 - 到)4487-4503
頁數17
期刊Journal of Cellular Physiology
237
發行號12
DOIs
出版狀態Published - 2022 12月

All Science Journal Classification (ASJC) codes

  • 生理學
  • 臨床生物化學
  • 細胞生物學

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