Medical Professional Publications

Blocking Signaling Pathway to Kill Liver Cancer

Studies Confirm Pathway Trigger and Identify Potential New Blocking Molecules

Research from Nationwide Children’s is helping to clarify how the most severe form of liver cancer develops and also has identified a potential new compound for boosting the effectiveness of its current treatments. 

Interleukin-6 (IL-6) is a molecule originally characterized as important in immune and inflammatory responses to protect cells under very toxic conditions.  A growing body of evidence has demonstrated that overproduction of IL-6 contributes to various human diseases including autoimmune disease, chronic inflammatory disease and many types of human cancer such as liver cancer.

“IL-6 levels in liver cancer patients are 25-fold higher than healthy adults,” said Jiayuh Lin, PhD, principal investigator in the Center for Childhood Cancer at The Research Institute and the studies’ lead author. “The high levels of IL-6 are associated with hepatocellular carcinoma (HCC), the most common and most life-threatening liver cancer.”

Only recently have studies documented the role IL-6 plays in promoting cancer development.  Data indicates that tumor development caused by STAT3, a major signaling pathway for cancer inflammation, is mediated by IL-6 signaling. 

To clarify the role IL-6 plays on STAT3 signaling and liver tumor cell survival, investigators from Nationwide Children’s Hospital and The Ohio State University, examined human liver cancer cell lines. When IL-6 was added to the human liver cancer cells, STAT3 was activated by IL-6, and cancer cells became more resistant to the cytotoxic effects of doxorubicin, a drug commonly used in cancer chemotherapy.

In an attempt to interrupt this promotion of cell survival by IL-6, Yan Liu, a post-doctoral research fellow in Dr. Lin’s laboratory then treated the cells with LLL12, a small molecule shown to inhibit the STAT3 pathway.  They found that blocking STAT3 signaling using a small molecule inhibitor seemed to reduce IL-6’s power to protect the liver cancer cells from killing by doxorubicin.  These findings appear in the August issue of the Journal of Biological Chemistry.   In another recent publication, appearing in Cell Cycle, Dr. Lin’s team showed that a curcumin analogue that selectively inhibits STAT3, known as FLL32 can also to block IL-6’s ability to activate STAT3, providing another potential therapy to use with existing anti-cancer drugs.

“Our findings indicate that IL-6/STAT3 signaling is an important survival pathway in liver cancer cells and can promote drug-resistance of cancer cells,” said Dr. Lin.  “Blocking IL-6/STAT3 with small molecules like FLLL32 may make liver cancer cells more sensitive to chemotherapeutic agents and improve cancer treatment.” Both small molecular compounds, LLL12 and FLLL32, have been filed from Nationwide Children’s and OSU for patent applications.

Liu Y, Li PK, Li C, Lin J. Inhibition of STAT3 signaling blocks the anti-apoptotic activity of IL-6 in human liver cancer cells. J Biol Chem. 2010 Aug 27;285(35):27429-39.

Liu Y, Fuchs J, Li C, Lin J. IL-6, a risk factor for hepatocellular carcinoma: FLLL32 inhibits IL-6-induced STAT3 phosphorylation in human hepatocellular cancer cells. Cell Cycle. 2010, 9(17), 1

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