2. Academic Validation
  3. 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to inhibit hepatocellular carcinoma cells

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

  • Biochem Biophys Res Commun. 2016 Mar 4;471(2):267-73. doi: 10.1016/j.bbrc.2016.01.030.
Meili Fu 1,  Fuqiang Wan 2,  Zhengling Li 3,  Fenghua Zhang 4
Affiliations

Affiliations

  • 1 Department of Infectious Disease, Linyi People's Hospital, Linyi 276000, China. Electronic address: fumeilidrlinyi@tom.com.
  • 2 Department of Head and Neck Surgery, Linyi Tumor Hospital, Linyi 276000, China.
  • 3 Department of Nursing, Tengzhou Central People's Hospital, Tengzhou 277500, China.
  • 4 Department of Operating Room, Linyi People's Hospital, Linyi 276000, China.
PMID: 26773495 DOI: 10.1016/j.bbrc.2016.01.030
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 stable knockdown by targeted-shRNAs largely inhibited 4SC-202-induced mPTP opening, cytochrome C release, and following HCC cell apoptotic death. Together, we suggest that 4SC-202 activates ASK1-dependent mitochondrial Apoptosis pathway to potently inhibit human HCC cells.

Keywords

4SC-202; ASK1 and cyclophilin-D; HDAC inhibitor; Hepatocellular carcinoma (HCC); Mitochondrial apoptosis pathway.

Figures
Products