title: LB-100 sensitizes hepatocellular carcinoma cells to the effects of sorafenib during hypoxia by activation of Smad3 phosphorylation.
abstract: Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis. The multikinase inhibitor sorafenib is the only clinically proved systematic treatment for HCC. However, few patients respond to sorafenib. Hypoxic microenvironments contribute to sorafenib resistance. LB-100, a serine/threonine protein phosphatase 2A (PP2A) inhibitor was previously found to be a chemosensitizer in HCC. Here, we tested whether LB-100 could sensitize HCC to the effects of sorafenib. Intriguingly, LB-100 enhanced the effects of sorafenib in HCC cells only during hypoxic environments. LB-100 dramatically increased intracellular p-Smad3 level, which was responsible for the effect of LB-100 as a sensitizer. LB-100 downregulated Bcl-2 expression and enhanced sorafenib-induced apoptosis in HCC cells. We further proved that PP2A mediated LB-100-induced p-Smad3 overexpression. In addition, p38 mitogen-activated protein kinase pathway was activated in hypoxic conditions, and enhanced p-Smad3-dependent Bcl-2 inhibition and consequent apoptosis. In conclusion, LB-100 sensitized HCC cells to sorafenib in hypoxic environments. This effect was mediated by inactivation of PP2A, resulting in enhanced level of p-Smad3. Increased p-Smad3 downregulated Bcl-2, causing increased apoptosis of HCC cells.
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, China.
authors.forename: Qi-Han
authors.initials: QH
authors.lastname: Fu
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, China.|Key Laboratory of Cancer Prevention and Intervention, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, China.
authors.forename: Jing-Ying
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Huzhou Central Hospital, Huzhou, 313003, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, China.
authors.forename: Guo-Gang
authors.initials: GG
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China.
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, China. shirleybai57@hotmail.com.|Key Laboratory of Cancer Prevention and Intervention, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China. shirleybai57@hotmail.com.
authors.forename: Xue-Li
authors.initials: XL
authors.lastname: Bai
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou, 310009, China. liangtingbo@zju.edu.cn.|Collaborative Innovation Center for Cancer Medicine, Zhejiang University, Guangzhou, 510000, China. liangtingbo@zju.edu.cn.
authors.forename: Ting-Bo
authors.initials: TB
authors.lastname: Liang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011897:Random Allocation; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C000708580:LB100; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D009536:Niacinamide; D000077157:Sorafenib; D054648:Protein Phosphatase 2
keywords: Apoptosis; Drug resistance; PP2A; p-Smad3; p38 MAPK