Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cholesterol-metabolism study suggests new diagnostic, treatment approach for aggressive prostate cancer

05.03.2014

Researchers have discovered a link between prostate cancer aggressiveness and the accumulation of a compound produced when cholesterol is metabolized in cells, findings that could bring new diagnostic and treatment methods.

Findings also suggest that a class of drugs previously developed to treat atherosclerosis might be repurposed for treatment of advanced prostate cancer.


Researchers have discovered a link between prostate cancer aggressiveness and a compound called cholesteryl ester accumulated in lipid droplets inside single cancer cells. This image shows liver metastasis of human prostate cancer, taken using a technique called stimulated Raman scattering microscopy. The bright dots represent intracellular lipid droplets enriched in cholesteryl ester. (Purdue University image)

The research showed depletion of the compound cholesteryl ester significantly reduced prostate cancer cell proliferation, impaired its ability to invade a laboratory tissue culture and suppressed tumor growth in mice. "Our study provides an avenue towards diagnosis of aggressive prostate cancer. Moreover, we showed that depleting cholesteryl ester significantly impairs prostate cancer aggressiveness," said Ji-Xin Cheng, a professor in Purdue University's Weldon School of Biomedical Engineering and Department of Chemistry.

The research involved analysis of clinical samples harvested from prostate cancer patients, specialized cell lines and mice.

Findings are detailed in a research paper appearing Tuesday (March 4) in the journal Cell Metabolism. The paper was authored by researchers associated with Purdue's Center for Cancer Research and the Indiana University Melvin and Bren Simon Cancer Center at Indiana University School of Medicine.

"Prostate cancer is the second-leading cause of cancer-related mortality in American men. Our finding offers a biological foundation that supports the beneficial effect of cholesterol-lowering drugs. Second, our study heralds the potential of using cholesteryl ester as a therapeutic target for advanced prostate cancer," said study co-author Timothy Ratliff, the Robert Wallace Miller Director of Purdue's Center for Cancer Research. "These results together suggest that cholesteryl ester accumulation might be used for more accurate prediction of prostate cancer aggressiveness, if validated through further examination of a large number of tissue biopsies and correlation assessment of cholesteryl ester levels and clinical outcomes of patients."

A critical focus of the research is the analysis of individual lipid droplets inside single cells. Purdue researchers have developed an analytical tool called Raman spectromicroscopy that allows compositional analysis of single lipid droplets in living cells and mice.

"It is conceivable that cancer cells require reservoirs for lipids, namely lipid droplets. However, our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases," Cheng said.

The researchers learned that cholesteryl ester accumulation, which occurs only in advanced prostate cancer and its metastasis, results from the loss of a tumor-suppressing gene called PTEN and the activation of an intracellular metabolic pathway promoting tumor growth.

"These findings improve current understanding of the role of cholesterol in cancer and also suggest new opportunities for the diagnosis and treatment of aggressive prostate cancer. We have been pleased to be able to collaborate with Dr. Cheng on his important research" said Michael Koch, John P. Donohue Professor of Urology and chair of the Department of Urology at IU School of Medicine.

Findings show the drugs avasimibe and Sandoz 58-035 reduced the accumulation of cholesteryl ester and significantly hindered advanced prostate cancer growth in laboratory cell cultures and xenograft mouse models. These drugs did not show toxicity to animals.

"We note that avasimibe, Sandoz 58-035 and a class of similar drugs were developed to treat atherosclerosis, but the clinical trials were halted due to the lack of effectiveness in reducing plaque size," Cheng said. "The present study highlights a novel use of these drugs to treat advanced prostate cancer."

The paper was authored by Purdue doctoral students Shuhua Yue, Junjie Li, Seung-Young Lee and Hyeon Jeong Lee; Purdue postdoctoral research assistants Tian Shao and Bing Song; Liang Cheng, professor of pathology and laboratory medicine and urology at the IU School of Medicine; Timothy A. Masterson, an assistant professor of urology at the IU School Medicine; Xiaoqi Liu, an associate professor in Purdue's Department of Biochemistry; Ratliff, a professor of comparative pathobiology; and Cheng.

The research was supported by the Walther Cancer Foundation, National Institutes of Health, National Science Foundation and the Department of Defense. 

Writer: Emil Venere, 765-494-4709, venere@purdue.edu 

Sources:  Ji-Xin Cheng, 765-494-4335, jcheng@purdue.edu

Timothy Ratliff, 765-494-9129, tlratliff@purdue.edu

Mary Hardin, IU Communications, 317-274-5456, mhardin@iu.edu 

Note to Journalists: An electronic copy of the research paper is available by contacting Emil Venere, 765-494-4709, venere@purdue.edu.


ABSTRACT

Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness

Shuhua Yue1, Junjie Li2, Seung-Young Lee1, Hyeon Jeong Lee3, Tian Shao4, Bing Song2, Liang Cheng5, Timothy A. Masterson6, Xiaoqi Liu4, 7, Timothy L. Ratliff 3,7, Ji-Xin Cheng1,7*

1 Weldon School of Biomedical Engineering, Purdue University

2 Department of Biological Sciences, Purdue University

3 Department of Comparative Pathobiology, Purdue University,

4 Department of Biochemistry, Purdue University

5 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine

6 Department of Urology, Indiana University School of Medicine

7 Center for Cancer Research, Purdue University

* Corresponding author: jcheng@purdue.edu, 765-494-433

Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism.


Emil Venere | EurekAlert!

Further reports about: Department Hyeon Medicine PTEN atherosclerosis cholesterol drugs metabolism proliferation prostate toxicity

More articles from Health and Medicine:

nachricht Mobile phone test can reveal vision problems in time
11.02.2016 | University of Gothenburg

nachricht Proteomics and precision medicine
08.02.2016 | University of Iowa Health Care

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Production of an AIDS vaccine in algae

Today, plants and microorganisms are heavily used for the production of medicinal products. The production of biopharmaceuticals in plants, also referred to as “Molecular Pharming”, represents a continuously growing field of plant biotechnology. Preferred host organisms include yeast and crop plants, such as maize and potato – plants with high demands. With the help of a special algal strain, the research team of Prof. Ralph Bock at the Max Planck Institute of Molecular Plant Physiology in Potsdam strives to develop a more efficient and resource-saving system for the production of medicines and vaccines. They tested its practicality by synthesizing a component of a potential AIDS vaccine.

The use of plants and microorganisms to produce pharmaceuticals is nothing new. In 1982, bacteria were genetically modified to produce human insulin, a drug...

Im Focus: The most accurate optical single-ion clock worldwide

Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock which attains an accuracy which had only been predicted theoretically so far. Their optical ytterbium clock achieved a relative systematic measurement uncertainty of 3 E-18. The results have been published in the current issue of the scientific journal "Physical Review Letters".

Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock...

Im Focus: Goodbye ground control: autonomous nanosatellites

The University of Würzburg has two new space projects in the pipeline which are concerned with the observation of planets and autonomous fault correction aboard satellites. The German Federal Ministry of Economic Affairs and Energy funds the projects with around 1.6 million euros.

Detecting tornadoes that sweep across Mars. Discovering meteors that fall to Earth. Investigating strange lightning that flashes from Earth's atmosphere into...

Im Focus: Flow phenomena on solid surfaces: Physicists highlight key role played by boundary layer velocity

Physicists from Saarland University and the ESPCI in Paris have shown how liquids on solid surfaces can be made to slide over the surface a bit like a bobsleigh on ice. The key is to apply a coating at the boundary between the liquid and the surface that induces the liquid to slip. This results in an increase in the average flow velocity of the liquid and its throughput. This was demonstrated by studying the behaviour of droplets on surfaces with different coatings as they evolved into the equilibrium state. The results could prove useful in optimizing industrial processes, such as the extrusion of plastics.

The study has been published in the respected academic journal PNAS (Proceedings of the National Academy of Sciences of the United States of America).

Im Focus: New study: How stable is the West Antarctic Ice Sheet?

Exceeding critical temperature limits in the Southern Ocean may cause the collapse of ice sheets and a sharp rise in sea levels

A future warming of the Southern Ocean caused by rising greenhouse gas concentrations in the atmosphere may severely disrupt the stability of the West...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Symposium on Climate Change Adaptation in Africa 2016

12.02.2016 | Event News

Travel grants available: Meet the world’s most proficient mathematicians and computer scientists

09.02.2016 | Event News

AKL’16: Experience Laser Technology Live in Europe´s Largest Laser Application Center!

02.02.2016 | Event News

 
Latest News

LIGO confirms RIT's breakthrough prediction of gravitational waves

12.02.2016 | Physics and Astronomy

Gene switch may repair DNA and prevent cancer

12.02.2016 | Life Sciences

Using 'Pacemakers' in spinal cord injuries

12.02.2016 | Medical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>