ACY-241, an HDAC6 inhibitor, overcomes erlotinib resistance in human pancreatic cancer cells by inducing autophagy.
Seong-Jun ParkSang Hoon JooNaeun LeeWon-Jun JangJi Hae SeoChul-Ho JeongPublished in: Archives of pharmacal research (2021)
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.
Keyphrases
- cell death
- cell cycle arrest
- histone deacetylase
- endoplasmic reticulum stress
- induced apoptosis
- advanced non small cell lung cancer
- epidermal growth factor receptor
- oxidative stress
- signaling pathway
- diabetic rats
- high glucose
- endothelial cells
- pi k akt
- mesenchymal stem cells
- stem cells
- endoplasmic reticulum
- single cell
- skeletal muscle
- dna damage
- deep learning
- machine learning
- big data
- replacement therapy
- protein protein