Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Dec;237(12):4487-4503.
doi: 10.1002/jcp.30898. Epub 2022 Oct 17.

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

Yu-Ying Chao  1   2 , Bu-Miin Huang  2   3 , I-Chen Peng  4 , Pei-Rong Lee  1   2 , Yi-Shyun Lai  5 , Wen-Tai Chiu  5 , Yi-Syuan Lin  1 , Shih-Chieh Lin  1   6   7 , Jung-Hsuan Chang  4 , Pai-Sheng Chen  1   8 , Shaw-Jenq Tsai  1   7 , Chia-Yih Wang  1   2
Affiliations

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

Yu-Ying Chao et al. J Cell Physiol. 2022 Dec.

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.

Keywords: DNA damage response; autophagy; centriolar satellites; chemoresistance; pancreatic ductal adenocarcinoma; primary cilia.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

REFERENCES

    1. An, J., Yang, D. Y., Xu, Q. Z., Zhang, S. M., Huo, Y. Y., Shang, Z. F., Wang, Y., Wu, D. C., & Zhou, P. K. (2008). DNA-dependent protein kinase catalytic subunit modulates the stability of c-Myc oncoprotein. Molecular Cancer, 7, 32. https://doi.org/10.1186/1476-4598-7-32
    1. Andreassen, P. R., D'Andrea, A. D., & Taniguchi, T. (2004). ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes & Development, 18(16), 1958-1963. https://doi.org/10.1101/gad.1196104
    1. Chen, T. Y., Huang, B. M., Tang, T. K., Chao, Y. Y., Xiao, X. Y., Lee, P. R., Yang, L. Y., & Wang, C. Y. (2021). Genotoxic stress-activated DNA-PK-p53 cascade and autophagy cooperatively induce ciliogenesis to maintain the DNA damage response. Cell Death & Differentiation, 28(6), 1865-1879. https://doi.org/10.1038/s41418-020-00713-8
    1. Chen, T. Y., Lin, T. C., Kuo, P. L., Chen, Z. R., Cheng, H., Chao, Y. Y., Syu, J. S., Lu, F. I., & Wang, C. Y. (2021). Septin 7 is a centrosomal protein that ensures S phase entry and microtubule nucleation by maintaining the abundance of p150(glued). Journal of Cellular Physiology, 236(4), 2706-2724. https://doi.org/10.1002/jcp.30037
    1. Corbit, K. C., Aanstad, P., Singla, V., Norman, A. R., Stainier, D. Y. R., & Reiter, J. F. (2005). Vertebrate smoothened functions at the primary cilium. Nature, 437(7061), 1018-1021. https://doi.org/10.1038/nature04117

Publication types

MeSH terms

LinkOut - more resources