Featured Research

from universities, journals, and other organizations

Blocking an oncogene in liver cancer could be potential therapy option

Date:
October 13, 2010
Source:
Ohio State University
Summary:
Scientists have found that a synthetic molecule they designed can block activation of a gene in liver cancer cells, halting a process that allows some of those cancer cells to survive chemotherapy. Without the interference of this gene's function, certain liver cancer cells appear to be protected from the toxic effects of chemotherapy drugs.

Scientists have found that a synthetic molecule they designed can block activation of a gene in liver cancer cells, halting a process that allows some of those cancer cells to survive chemotherapy.

Related Articles


Without the interference of this gene's function, certain liver cancer cells appear to be protected from the toxic effects of chemotherapy drugs.

Blocking the oncogene, called STAT3, prevents a protein from protecting the cells, the research suggests. As a result, more liver cancer cells succumb to treatment.

Researchers hope an anti-cancer drug based on the molecule's design eventually will be developed for use in patients, after the required animal and clinical testing is completed.

The scientists have seen similar results in studies using this experimental molecule, called LLL12, to block STAT3 as a way to induce cell death in breast and pancreatic cancer cells.

"For patients, it would be easy to use an intravenous drug based on this small molecule, which is relatively cheap and easy to manufacture," said Jiayuh Lin, senior author of the study and an associate professor of pediatrics at Ohio State University.

"We also have seen signs that blocking STAT3 could block other downstream targets, and could affect other STAT3-regulated genes that can turn normal cells into cancer cells. We believe this molecule has a lot of potential for cancer therapy."

Lin led the team of scientists who designed LLL12 using powerful computers and a computational method called structure-based design. The group reported on its creation earlier this year.

This new study is published in a recent issue of the Journal of Biological Chemistry.

The protein in this process is called interleukin-6, or IL-6. It is a cytokine, a chemical messenger that causes inflammation, and can have both beneficial and damaging effects in the body. Previous research by other scientists has shown that high levels of IL-6 in the blood are associated with hepatocellular carcinoma, the most common type of liver cancer.

The fifth most common cancer in humans, liver cancer remains one of the most difficult to successfully treat. Patients' overall five-year survival rate is about 10 percent, according to the American Cancer Society.

In this study, the researchers observed that liver cancer cells known to be resistant to a common chemotherapy drug, doxorubicin, had higher levels of IL-6 than did other liver cancer cells -- an indication that the protein likely fosters the drug resistance. Subsequent tests showed that these resistant cells with high IL-6 also had higher levels of STAT3 phosphorylation than did other cells.

To further demonstrate this relationship between the protein and cell survival, Lin and colleagues pretreated liver cancer cells with the chemotherapy drug and then followed with different doses of IL-6. The addition of IL-6 rescued these cells from chemo-induced death.

Alternately, when the scientists introduced an antibody to inhibit IL-6 in drug-resistant cancer cells and then followed with doses of doxorubicin, 70 percent more of the cells treated with the IL-6 inhibitor died compared to cells treated with the chemo drug alone -- a sign that the loss of IL-6 lowers survival in these particular cancer cells.

After determining in cell cultures that IL-6 activates STAT3 to help perform this cell survival function, the researchers focused on testing the effects of blocking the gene alone.

They first used silencing RNA, or siRNA, to prevent activation of the STAT3. More of the siRNA-treated cells died than did cells in which the STAT3 was not blocked.

"At this point, we know that STAT3 plays an important role, and that IL-6 depends on STAT3 to protect cells from dying," said Lin, also an investigator in Ohio State's Comprehensive Cancer Center and the Center for Childhood Cancer at Nationwide Children's Hospital.

The scientists then turned to the synthetic molecule, LLL12, which was designed specifically to tuck itself into a gap in STAT3's two-part structure and disable its activation.

The researchers introduced LLL12 to four types of liver cancer cells and followed with a dose of IL-6. The IL-6 protein had no protective effect on cells treated with the molecule, meaning it could not turn on STAT3, a required step in protecting the cells from death.

To be sure, they also tested how cells with and without LLL12 treatment responded to chemotherapy. The small molecule treatment completely blocked resistance to the drug, Lin said, even in the types of liver cancer cells that express the highest IL-6 levels and are most resistant to doxorubicin.

Importantly, the researchers were able to determine that inhibiting STAT3 activation did not affect other proteins that are induced by IL-6 for potentially beneficial reasons. The small molecule also did not exacerbate the effects of chemotherapy on normal liver cells.

Lin and colleagues are currently testing the effects of LLL12 in multiple myeloma, breast and colon cancer cells, in which the IL-6/STAT3 pathway also plays an important role.

This work was supported by the grants from the National Institutes of Health, the Pancreatic Cancer Action Network -- American Association of Cancer Research, and the National Foundation for Cancer Research.

Co-authors of the study include Yan Liu of the Department of Pediatrics, and Pui-Kai Li and Chenglong Li of the Division of Medicinal Chemistry and Pharmacognosy, all at Ohio State.


Story Source:

The above story is based on materials provided by Ohio State University. The original article was written by Emily Caldwell. Note: Materials may be edited for content and length.


Journal Reference:

  1. Y. Liu, P.-K. Li, C. Li, J. Lin. Inhibition of STAT3 Signaling Blocks the Anti-apoptotic Activity of IL-6 in Human Liver Cancer Cells. Journal of Biological Chemistry, 2010; 285 (35): 27429 DOI: 10.1074/jbc.M110.142752

Cite This Page:

Ohio State University. "Blocking an oncogene in liver cancer could be potential therapy option." ScienceDaily. ScienceDaily, 13 October 2010. <www.sciencedaily.com/releases/2010/10/101012163303.htm>.
Ohio State University. (2010, October 13). Blocking an oncogene in liver cancer could be potential therapy option. ScienceDaily. Retrieved November 28, 2014 from www.sciencedaily.com/releases/2010/10/101012163303.htm
Ohio State University. "Blocking an oncogene in liver cancer could be potential therapy option." ScienceDaily. www.sciencedaily.com/releases/2010/10/101012163303.htm (accessed November 28, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Friday, November 28, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Rural India's Low-Cost Sanitary Pad Revolution

Rural India's Low-Cost Sanitary Pad Revolution

AFP (Nov. 28, 2014) — One man hopes his invention -– a machine that produces cheap sanitary pads –- will help empower Indian women. Duration: 01:51 Video provided by AFP
Powered by NewsLook.com
Research on Bats Could Help Develop Drugs Against Ebola

Research on Bats Could Help Develop Drugs Against Ebola

AFP (Nov. 28, 2014) — In Africa's only biosafety level 4 laboratory, scientists have been carrying out experiments on bats to understand how virus like Ebola are being transmitted, and how some of them resist to it. Duration: 01:18 Video provided by AFP
Powered by NewsLook.com
WHO Says Male Ebola Survivors Should Abstain From Sex

WHO Says Male Ebola Survivors Should Abstain From Sex

Newsy (Nov. 28, 2014) — WHO cites four studies that say Ebola can still be detected in semen up to 82 days after the onset of symptoms. Video provided by Newsy
Powered by NewsLook.com
Ebola Leaves Orphans Alone in Sierra Leone

Ebola Leaves Orphans Alone in Sierra Leone

AFP (Nov. 27, 2014) — The Ebola epidemic sweeping Sierra Leone is having a profound effect on the country's children, many of whom have been left without any family members to support them. Duration: 01:02 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins