Hexabromocyclododecane and polychlorinated biphenyls increase resistance of hepatocellular carcinoma cells to cisplatin through the phosphatidylinositol 3-kinase/protein kinase B pathway.

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers in China with high mortality, high chemotherapy resistance incidence, and poor prognosis. This study aimed to investigate the influence of polychlorinated biphenyls (PCBs) and hexabromocyclododecane (HBCD) on chemoresistance of HCC cells (HepG2, MHCC97H, and MHCC97L) to cisplatin and to explore the potential molecular mechanism. Cell viability, DNA damage, the expression level and activity of nuclear factor-κB (NF-κB), p53/Mdm4, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway were measured. The results showed that HBCD and PCBs could significantly reduce the chemosensitivity of HCC cells to cisplatin, increasing the cell viability and decreasing DNA damage. Moreover, HBCD and PCBs could induce the transcriptional activity of NF-κb and suppress the p53 expression in HepG2 and MHCC97H cells. In MHCC97L cells, however, opposite changes for NF-κB protein expression, NF-κB transcriptional activity, and p53/Mdm4 expression were observed after HBCD and PCBs exposure. Further investigation revealed that HBCD and PCBs exposure significantly increased the expression level of p-Akt and mammalian target of rapamycin (mTOR) in HepG2 and MHCC97H cells, but reduced that in MHCC97L cells. PI3K inhibitor LY294002 could relieve the influence of HBCD and PCBs on chemoresistance in HepG2 and MHCC97H cells. Taken together, HBCD and PCBs at low concentrations could increase the resistance of HCC cells to cisplatin through modulation on NF-κB pathway activation and p53 function, which is associated with the activity of PI3K/Akt pathway.

• Authors: Jing An, Xiu Wang, Panpan Guo, Yufang Zhong, Xinyu Zhang, Zhiqiang Yu
• Journal: Toxicology letters (Toxicol Lett) Vol. 229 Issue 1 Pg. 265-72 (Aug 17 2014) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 24960055 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• Environmental Pollutants
• Hydrocarbons, Brominated
• Indicators and Reagents
• MDM4 protein, human
• NF-kappa B
• Nuclear Proteins
• Proto-Oncogene Proteins
• Tumor Suppressor Protein p53
• hexabromocyclododecane
• Polychlorinated Biphenyls
• Oncogene Protein v-akt
• Proto-Oncogene Proteins c-akt
• Alkaline Phosphatase
• Cisplatin

Topics

• Alkaline Phosphatase (metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Cycle Proteins
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cisplatin (pharmacology)
• Comet Assay
• Drug Resistance, Neoplasm (drug effects)
• Environmental Pollutants (toxicity)
• Humans
• Hydrocarbons, Brominated (toxicity)
• Indicators and Reagents
• Liver Neoplasms, Experimental (drug therapy, metabolism)
• NF-kappa B (drug effects, genetics)
• Nuclear Proteins (drug effects)
• Oncogene Protein v-akt (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (drug effects)
• Polychlorinated Biphenyls (toxicity)
• Proto-Oncogene Proteins (drug effects)
• Proto-Oncogene Proteins c-akt (drug effects)
• Signal Transduction (drug effects)
• Tumor Suppressor Protein p53 (genetics, metabolism)