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ACY-241, an HDAC6 inhibitor, overcomes erlotinib resistance in human pancreatic cancer cells by inducing autophagy

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Author(s)
Seong-Jun ParkSang Hoon JooNaeun LeeWon-Jun JangJi Hae SeoChul-Ho Jeong
Keimyung Author(s)
Seo, Ji Hye
Department
Dept. of Biochemistry (생화학)
Journal Title
Arch Pharm Res
Issued Date
2021
Volume
44
Keyword
AutophagyCombination therapyEGFR-TKI resistanceHDAC6ACY-241
Abstract
Histone deacetylase 6 (HDAC6) is a promising target for cancer treatment because it regulates cell mobility, protein trafficking, cell growth, apoptosis, and metastasis. However, the mechanism of HDAC6-induced anticancer drug resistance is unclear. In this study, we evaluated the anticancer effect of ACY-241, an HDAC6-selective inhibitor, on erlotinib-resistant pancreatic cancer cells that overexpress HDAC6. Our data revealed that ACY-241 hyperacetylated the HDAC6 substrate, α-tubulin, leading to a significant reduction in cell viability of erlotinib-resistant pancreatic cells, BxPC3-ER and HPAC-ER. Notably, a synergistic anticancer effect was observed in cells that received combined treatment with ACY-241 and erlotinib. Combined treatment effectively induced autophagy and inhibited autophagy through siLC3B, and siATG5 alleviated ACY-241-mediated cell death, as reflected by the recovery of PARP cleavage and apoptosis rates. In addition, combined ACY-241 and erlotinib treatment induced autophagy and subsequently, cell death by reducing AKT–mTOR activity and increasing phospho-AMPK signaling. Therefore, HDAC6 may be involved in the suppression of autophagy and acquisition of resistance to erlotinib in ER pancreatic cancer cells. ACY-241 to overcome erlotinib resistance could be an effective therapeutic strategy against pancreatic cancer.
Keimyung Author(s)(Kor)
서지혜
Publisher
School of Medicine (의과대학)
Citation
Seong-Jun Park et al. (2021). ACY-241, an HDAC6 inhibitor, overcomes erlotinib resistance in human pancreatic cancer cells by inducing autophagy. Arch Pharm Res, 44, 1062–1075. doi: 10.1007/s12272-021-01359-x
Type
Article
ISSN
1976-3786
Source
https://link.springer.com/article/10.1007/s12272-021-01359-x
DOI
10.1007/s12272-021-01359-x
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/44104
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Biochemistry (생화학)
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