Skip to Content
Merck
  • ATM- and ATR-induced primary ciliogenesis promotes cisplatin resistance in pancreatic ductal adenocarcinoma.

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

Journal of cellular physiology (2022-10-18)
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
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Roscovitine, ≥98% (TLC)
Sigma-Aldrich
Anti-γ-Tubulin antibody, Mouse monoclonal, clone GTU-88, ascites fluid
Sigma-Aldrich
Anti-ATG7 antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
p53-Snail binding Inhibitor, GN25, The p53-Snail binding Inhibitor, GN25 controls the biological activity of p53-Snail. This small molecule/inhibitor is primarily used for Neuroscience applications.
Sigma-Aldrich
KU-55933, ≥98% (HPLC)
Sigma-Aldrich
Gemcitabine hydrochloride, ≥98% (HPLC)
Sigma-Aldrich
Sodium orthovanadate, ≥90% (titration)
Sigma-Aldrich
Monoclonal Anti-Tubulin, Acetylated antibody produced in mouse, clone 6-11B-1, ascites fluid
Sigma-Aldrich
Caffeine, powder, ReagentPlus®
Sigma-Aldrich
Paclitaxel, from Taxus brevifolia, ≥95% (HPLC), powder
Sigma-Aldrich
Akt Inhibitor IV, The Akt Inhibitor IV, also referenced under CAS 681281-88-9, controls the biological activity of Akt. This small molecule/inhibitor is primarily used for Phosphorylation & Dephosphorylation applications.
Sigma-Aldrich
Chk2 Inhibitor II, Chk2 Inhibitor II, BML-277, CAS 516480-79-8 is a cell-permeable, potent, reversible, ATP-competitive inhibitor of Chk2 (IC₅₀ = 15 nM).
Sigma-Aldrich
Cisplatin, Cisplatin - CAS 15663-27-1, is a platinum coordination complex with potent anti-neoplastic activity. Induces apoptosis in cancer cells, possibly via caspase-3 activation.
Sigma-Aldrich
SBI-0206965, ≥98% (HPLC)
Sigma-Aldrich
Hydroxyurea, 98%, powder
Sigma-Aldrich
Etoposide, synthetic, 95.0-105.0%, powder