ArticleTumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine2016
LB-100 sensitizes hepatocellular carcinoma cells to the effects of sorafenib during hypoxia by activation of Smad3 phosphorylation.
Article in Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- MYC at the tumor-immune interface: mechanisms of immune escape and immunotherapy resistance.Frontiers in immunology · 2026Review
- Potential Treatment Strategies for Hepatocellular Carcinoma Cell Sensitization to Sorafenib.Journal of hepatocellular carcinoma · 2023Review
- Cellular Protein Phosphatase 2A Regulates Cell Survival Mechanisms in Influenza A Virus Infection.International journal of molecular sciences · 2021Article
- The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects.Signal transduction and targeted therapy · 2020Review
- The Antitumor Drug LB-100 Is a Catalytic Inhibitor of Protein Phosphatase 2A (PPP2CA) and 5 (PPP5C) Coordinating with the Active-Site Catalytic Metals in PPP5C.Molecular cancer therapeutics · 2019Article
- PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer.Advances in cancer research · 2019Review
- Targeting PP2A in cancer: Combination therapies.Biochimica et biophysica acta. Molecular cell research · 2019Review
- Primary tumor-derived exosomes facilitate metastasis by regulating adhesion of circulating tumor cells via SMAD3 in liver cancer.Oncogene · 2018Article
- Article
- Sorafenib induced alteration of protein glycosylation in hepatocellular carcinoma cells.Oncology letters · 2017Article
- The broken "Off" switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance.BBA clinical · 2016Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.