4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to inhibit hepatocellular carcinoma cells

Biochemical and Biophysical Research Communications
Fenghua ZhangFenghua Zhang

Abstract

The aim of the present study is to investigate the potential anti-hepatocellular carcinoma (HCC) cell activity by 4SC-202, a novel class I HDAC inhibitor (HDACi). The associated signaling mechanisms were also analyzed. We showed that 4SC-202 treatment induced potent cytotoxic and proliferation-inhibitory activities against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, adding 4SC-202 in HCC cells activated mitochondrial apoptosis pathway, which was evidenced by mitochondrial permeability transition pore (mPTP) opening, cytochrome C cytosol release and caspase-3/-9 activation. Inhibition of this apoptosis pathway, by caspase-3/-9 inhibitors, mPTP blockers, or by shRNA-mediated knockdown of cyclophilin-D (Cyp-D, a key component of mPTP), significantly attenuated 4SC-202-induced HCC cell death and apoptosis. Reversely, over-expression of Cyp-D enhanced 4SC-202's sensitivity in HCC cells. Further studies showed that 4SC-202 induced apoptosis signal-regulating kinase 1 (ASK1) activation, causing it translocation to mitochondria and physical association with Cyp-D. This mitochondrial ASK1-Cyp-D complexation appeared required for mediating 4SC-202-induced apoptosis activation. ASK1...Continue Reading

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Citations

Jun 18, 2016·Biochemical and Biophysical Research Communications·Xingang PengHaiyan Liu
Jul 9, 2016·Biochemical and Biophysical Research Communications·Yongsheng JiangBaoyou Sun
Sep 17, 2016·Cancer Biology & Therapy·Alexander BeckRoland Kappler
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Jun 10, 2021·European Journal of Medicinal Chemistry·Ying-Chao DuanYuan-Yuan Guan
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Apr 24, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Jiali YangGuanghui Wang

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Carcinoma, Hepatocellular

Hepatocellular Carcinoma is a malignant cancer in liver epithelial cells. Discover the latest research on Hepatocellular Carcinoma here.

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