The novel BH-3 mimetic apogossypolone induces Beclin-1-and ROS-mediated autophagy in human hepatocellular cells

被引：76

作者：

Cheng, P. ^{[1
]}

Ni, Z. ^{[1
]}

Dai, X. ^{[2
]}

Wang, B. ^{[1
]}

Ding, W. ^{[1
]}

Smith, A. Rae ^{[3
,4
]}

Xu, L. ^{[3
,4
]}

Wu, D. ^{[5
]}

He, F. ^{[1
]}

Lian, J. ^{[1
]}

机构：

[1] Third Mil Med Univ, Coll Basic Med Sci, Dept Biochem & Mol Biol, Chongqing 400038, Peoples R China

[2] Chongqing Normal Univ, Dept Educ Coll, Chongqing, Peoples R China

[3] Univ Kansas, Ctr Canc, Dept Mol Biosci, Lawrence, KS 66045 USA

[4] Univ Kansas, Ctr Canc, Dept Radiat Oncol, Lawrence, KS 66045 USA

[5] Xi An Jiao Tong Univ, Sch Life Sci & Technol, Educ Minist, Key Lab Biomed Informat Engn, Xian 710049, Peoples R China

来源：

CELL DEATH & DISEASE | 2013年 / 4卷

关键词：

ApoG2; ROS; autophagy; HCC;

D O I：

10.1038/cddis.2013.17

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Apogossypolone (ApoG2), a novel derivative of gossypol, exhibits superior antitumor activity in Bcl-2 transgenic mice, and induces autophagy in several cancer cells. However, the detailed mechanisms are not well known. In the present study, we showed that ApoG2 induced autophagy through Beclin-1- and reactive oxygen species (ROS)-dependent manners in human hepatocellular carcinoma (HCC) cells. Incubating the HCC cell with ApoG2 abrogated the interaction of Beclin-1 and Bcl-2/xL, stimulated ROS generation, increased phosphorylation of ERK and JNK, and HMGB1 translocation from the nucleus to cytoplasm while suppressing mTOR. Moreover, inhibition of the ROS-mediated autophagy by antioxidant N-acetyl-cysteine (NAC) potentiates ApoG2-induced apoptosis and cell killing. Our results show that ApoG2 induced protective autophagy in HCC cells, partly due to ROS generation, suggesting that antioxidant may serve as a potential chemosensitizer to enhance cancer cell death through blocking ApoG2-stimulated autophagy. Our novel insights may facilitate the rational design of clinical trials for Bcl-2-targeted cancer therapy. Cell Death and Disease (2013) 4, e489; doi: 10.1038/cddis.2013.17; published online 7 February 2013

引用

页码：e489 / e489

页数：7

共 46 条

[1]

El-Serag H.B., Rudolph K.L., Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis, Gastroenterology, 132, pp. 2557-2576, (2007)

[2]

Sherman M., Epidemiology of hepatocellular carcinoma, Oncology, 78, SUPPL. 1, pp. 7-10, (2010)

[3]

Tanaka S., Arii S., Molecular targeted therapies in hepatocellular carcinoma, Semin Oncol, 39, pp. 486-492, (2012)

[4]

Zender L., Spector M.S., Xue W., Flemming P., Cordon-Cardo C., Silke J., Et al., Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach, Cell, 125, pp. 1253-1267, (2006)

[5]

Levine B., Sinha S., Kroemer G., Bcl-2 family members: Dual regulators of apoptosis and autophagy, Autophagy, 4, pp. 600-606, (2008)

[6]

Kang M.H., Reynolds C.P., Bcl-2 inhibitors: Targeting mitochondrial apoptotic pathways in cancer therapy, Clin Cancer Res, 15, pp. 1126-1132, (2009)

[7]

Warr M.R., Shore G.C., Small-molecule Bcl-2 antagonists as targeted therapy in oncology, Curr Oncol, 15, pp. 256-261, (2008)

[8]

Sun Y., Wu J., Aboukameel A., Banerjee S., Arnold A.A., Chen J., Et al., Apogossypolone, a nonpeptidic small molecule inhibitor targeting Bcl-2 family proteins, effectively inhibits growth of diffuse large cell lymphoma cells in vitro and in vivo, Cancer Biol Ther, 7, pp. 1418-1426, (2008)

[9]

Arnold A.A., Aboukameel A., Chen J., Yang D., Wang S., Al-Katib A., Et al., Preclinical studies of Apogossypolone: A new nonpeptidic pan small-molecule inhibitor of Bcl-2, Bcl-XL and Mcl- 1 proteins in follicular small cleaved cell lymphoma model, Mol Cancer, 7, (2008)

[10]

Mi J.X., Wang G.F., Wang H.B., Sun X.Q., Ni X.Y., Zhang X.W., Et al., Synergistic antitumoral activity and induction of apoptosis by novel pan Bcl-2 proteins inhibitor apogossypolone with adriamycin in human hepatocellular carcinoma, Acta Pharmacol Sin, 29, pp. 1467-1477, (2008)

← 1 2 3 4 5 →