Oncotarget

Research Papers:

Suberoylanilide hydroxamic acid increases anti-cancer effect of tumor necrosis factor-α through up-regulation of TNF receptor 1 in lung cancer cells

Bo Ra You, Bo Ram Han and Woo Hyun Park _

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Oncotarget. 2017; 8:17726-17737. https://doi.org/10.18632/oncotarget.14628

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Abstract

Bo Ra You1, Bo Ram Han1, Woo Hyun Park1

1Department of Physiology, Medical School, Institute for Medical Sciences, Chonbuk National University, Jeonju, 561-180, Republic of Korea

Correspondence to:

Woo Hyun Park, email: parkwh71@chonbuk.ac.kr

Keywords: lung cancer, histone deacetylase, suberoylanilide hydroxamic acid, tumor necrosis factor-α, apoptosis

Received: December 08, 2015     Accepted: January 05, 2017     Published: January 13, 2017

ABSTRACT

Suberoylanilide hydroxamic acid (SAHA) as a histone deacetylase (HDAC) inhibitor has anti-cancer effect. Here, we evaluated the effect of SAHA on HDAC activity and cell growth in many normal lung and cancer cells. We observed that the HDAC activities of lung cancer cells were higher than that of normal lung cells. SAHA inhibited the growth of lung cancer cells regardless of the inhibitory effect on HDAC. This agent induced a G2/M phase arrest and apoptosis, which was accompanied by mitochondrial membrane potential (MMP: ΔΨm) loss in lung cancer cells. However, SAHA did not induce cell death in normal lung cells. All tested caspase inhibitors prevented apoptotic cell death in SAHA-treated A549 and Calu-6 lung cancer cells. Treatment with tumor necrosis factor-alpha (TNF-α) enhanced apoptosis in SAHA-treated lung cancer cells through caspase-8 and caspase-9 activations. Especially, SAHA increased the expression level of TNF-α receptor 1 (TNFR1), especially acetylation of the region of TNFR1 promoter -223/-29 in lung cancer cells. The down-regulation of TNFR1 suppressed apoptosis in TNF-α and SAHA-treated lung cancer cells. In conclusion, SAHA inhibited the growth of lung cancer cells via a G2/M phase arrest and caspase-dependent apoptosis. SAHA also enhanced apoptotic effect of TNF-α in human lung cancer cells through up-regulation of TNFR1. TNF-α may be a key to improve anti-cancer effect of HDAC inhibitors.


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