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

다국어 초록 (Multilingual Abstract)

Histone deacetylase 6 (HDAC6) is a promisingtarget for cancer treatment because it regulates cell mobility,protein traffi cking, cell growth, apoptosis, and metastasis.
However, the mechanism of HDAC6-induced anticancerdrug resistance is unclear. In this study, we evaluated theanticancer eff ect of ACY-241, an HDAC6-selective inhibitor,on erlotinib-resistant pancreatic cancer cells that overexpressHDAC6. Our data revealed that ACY-241 hyperacetylatedthe HDAC6 substrate, α-tubulin, leading to a signifi cantreduction in cell viability of erlotinib-resistant pancreaticcells, BxPC3-ER and HPAC-ER. Notably, a synergistic anticancereff ect was observed in cells that received combinedtreatment with ACY-241 and erlotinib. Combined treatmenteffectively induced autophagy and inhibited autophagythrough siLC3B, and siATG5 alleviated ACY-241-mediatedcell death, as refl ected by the recovery of PARP cleavageand apoptosis rates. In addition, combined ACY-241 and erlotinib treatment induced autophagy and subsequently,cell death by reducing AKT–mTOR activity and increasingphospho-AMPK signaling. Therefore, HDAC6 may beinvolved in the suppression of autophagy and acquisition ofresistance to erlotinib in ER pancreatic cancer cells. ACY-241 to overcome erlotinib resistance could be an eff ectivetherapeutic strategy against pancreatic cancer.

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