Navigation Links
Reviving a foe of cancer
Date:4/25/2013

April 25, 2013, New York, NY and Oxford, UK Cancer cells are a problem for the body because they multiply recklessly, refuse to die and blithely metastasize to set up shop in places where they don't belong. One protein that keeps healthy cells from behaving this way is a tumor suppressor named p53. This protein stops potentially precancerous cells from dividing and induces suicide in those that are damaged beyond repair. Not surprisingly, p53's critical function is disrupted in most cancers.

In the April 25 issue of Cancer Cell, a research team, led by Xin Lu, PhD, Ludwig director and member at the University of Oxford and a team of scientists from both institutions, describes how p53 is silenced in advanced melanomas by a protein named iASPP, and applies that information to restore p53 function in such cells.

Lu's research team first identified iASPP as an inhibitor of p53 in 2003. In the current study, Lu and her colleagues show that a protein complex named cyclin B1/cdk1, which is expressed at high levels in the cytoplasm of advanced melanomas, induces a pair of precise chemical modifications on iASPP to activate the protein. When activated, iASPP is shuttled into the nucleus, binds to p53 and ultimately inhibits its ability to induce cell suicide. "This is the first time that such a mechanism of p53 inactivation has been described," says Lu.

Lu and her colleagues explored whether they could restore p53's function in advanced melanomas by scuttling iASPP activation. To do so, they treated melanoma cells with a panel of small molecules and identified JNJ-7706621 (JNJ) as the best inhibitor of cyclinB1/cdk1. Lu's study showed that p53 is inhibited by two proteins in melanoma cells, iASPP and MDM2. The activity of the latter protein is known to be blocked by a small molecule called Nutlin-3. When JNJ and the Nutlin-3 were combined, the full function of p53 was restored in metastatic melanoma cells. Further, such treatment significantly suppressed tumor growth in mice.

"These results demonstrate that functional p53 in melanoma is normally inhibited by two different factors, instead of one, as previously thought. They also provide a proof of principle that both of those factors need to be blocked if p53 is to be successfully reactivated in cancer cells," said Lu.

Since multiple signaling pathways drive the growth of tumor cells, Lu and her colleagues wondered if the restoration of p53 function could be used as a strategy to enhance existing cancer therapies that target parallel signaling pathways. To find out, they treated advanced melanomas with JNJ, Nutlin-3 and a chemotherapeutic drug used in the clinic today named vemurafenib. This drug specifically inhibits BRAFV600E, a mutated protein that drives cancer cell proliferation. With such treatment, advanced melanoma tumors in preclinical mouse models shrank by a full 75 percent after 28 days of treatment. This has notable implications for the treatment of cancers in which p53 is not mutated but is instead functionally silencedroughly half of all cancer cases.

Based on their results, Lu and her colleagues argue that the best strategy in such cases might be to use drug combinations that target multiple, parallel pathways involved in tumor development and maintenance. Such combinations of drugs that normally have short-term efficacy could achieve an additive, if not a long-term synergistic effect.


'/>"/>

Contact: Rachel Steinhardt
rsteinhardt@licr.org
212-450-1582
Ludwig Institute for Cancer Research
Source:Eurekalert

Related biology news :

1. OHSU teams with Intel to decode the root causes of cancer and other complex diseases
2. Particular DNA changes linked with prostate cancer development and lethality
3. Cold winters freezing out breast cancer treatment
4. Identified as responsible for breast and ovarian hereditary cancer 3 mutations at BRCA1 gene
5. Ben-Gurion U. and Fox Chase Cancer Center awarded NIH measles grant
6. Researchers abuzz over caffeine as cancer-cell killer
7. An important discovery in breast cancer by IRCM researchers
8. UCLA researchers find nanodiamonds could improve effectiveness of breast cancer treatment
9. Icy therapy spot treats cancer in the lung
10. IMPAKT -- Translational research breast cancer conference
11. LSUHSC research discovers new drug target for metastatic breast cancer
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/11/2017)... -- NXT-ID, Inc. (NASDAQ:   NXTD ) ("NXT-ID" ... of independent Directors Mr. Robin D. Richards and ... furthering the company,s corporate governance and expertise. ... Gino Pereira , Chief Executive Officer ... guidance and benefiting from their considerable expertise as we move ...
(Date:4/5/2017)... April 5, 2017  The Allen Institute for Cell ... Explorer: a one-of-a-kind portal and dynamic digital window into ... data, the first application of deep learning to create ... cell lines and a growing suite of powerful tools. ... these and future publicly available resources created and shared ...
(Date:4/5/2017)... LONDON , April 4, 2017 KEY ... is anticipated to expand at a CAGR of 25.76% ... neurodegenerative diseases is the primary factor for the growth ... full report: https://www.reportbuyer.com/product/4807905/ MARKET INSIGHTS The ... of product, technology, application, and geography. The stem cell ...
Breaking Biology News(10 mins):
(Date:10/12/2017)... , ... October 12, 2017 ... ... announces publication of a United States multicenter, prospective clinical study that demonstrates ... point-of-care diagnostic test capable of identifying clinically significant acute bacterial and viral ...
(Date:10/12/2017)... ... October 12, 2017 , ... ... launched Rosalind™, the first-ever genomics analysis platform specifically designed for life science ... in honor of pioneering researcher Rosalind Franklin, who made a major contribution ...
(Date:10/11/2017)... (PRWEB) , ... October 11, 2017 , ... Personal eye wash is a basic first ... eye at a time. So which eye do you rinse first if a dangerous substance ... Plum Duo Eye Wash with its unique dual eye piece. , “Whether its ...
(Date:10/11/2017)... BioMarketing, a leading provider of patient support solutions, has announced ... network, which will launch this week. The VMS CNEs will ... to enhance the patient care experience by delivering peer-to-peer education ... professionals to help women who have been diagnosed and are ... ...
Breaking Biology Technology: