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

被引：12

作者：

Chao, Yu-Ying ^{[1
,2
]}

Huang, Bu-Miin ^{[2
,3
]}

Peng, I-Chen ^{[4
]}

Lee, Pei-Rong ^{[1
,2
]}

Lai, Yi-Shyun ^{[5
]}

Chiu, Wen-Tai ^{[5
]}

Lin, Yi-Syuan ^{[1
]}

Lin, Shih-Chieh ^{[1
,6
,7
]}

Chang, Jung-Hsuan ^{[4
]}

Chen, Pai-Sheng ^{[1
,8
]}

Tsai, Shaw-Jenq ^{[1
,7
]}

Wang, Chia-Yih ^{[1
,2
]}

机构：

[1] Natl Cheng Kung Univ, Coll Med, Inst Basic Med Sci, Tainan, Taiwan

[2] Natl Cheng Kung Univ, Dept Cell Biol & Anat, Tainan, Taiwan

[3] China Med Univ, China Med Univ Hosp, Dept Med Res, Taichung, Taiwan

[4] Natl Cheng Kung Univ, Dept Life Sci, Tainan, Taiwan

[5] Natl Cheng Kung Univ, Dept Biomed Engn, Tainan, Taiwan

[6] Natl Cheng Kung Univ, Coll Med, Inst Mol Med, Tainan, Taiwan

[7] Natl Cheng Kung Univ, Coll Med, Dept Physiol, Tainan, Taiwan

[8] Natl Cheng Kung Univ, Coll Med, Dept Med, Lab Sci & Biotechnol, Tainan, Taiwan

来源：

JOURNAL OF CELLULAR PHYSIOLOGY | 2022年 / 237卷 / 12期

关键词：

autophagy; centriolar satellites; chemoresistance; DNA damage response; pancreatic ductal adenocarcinoma; primary cilia; DNA-DAMAGE RESPONSE; CENTRIOLAR SATELLITE; PRIMARY CILIUM; PROTEIN; CENTROSOME; CANCER; INHIBITION; MECHANISMS; AUTOPHAGY; CELLS;

D O I：

10.1002/jcp.30898

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

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.

引用

页码：4487 / 4503

页数：17

共 46 条

[1] DNA-dependent protein kinase catalytic subunit modulates the stability of c-Myc oncoprotein [J].