Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Jamming a protein signal forces cancer cells to devour themselves

04.04.2014

Inhibiting cancer-promoting prolactin causes unconventional cell death in preclinical research

Under stress from chemotherapy or radiation, some cancer cells dodge death by consuming a bit of themselves, allowing them to essentially sleep through treatment and later awaken as tougher, resistant disease.

Interfering with a single cancer-promoting protein and its receptor can turn this resistance mechanism into lethal, runaway self-cannibalization, researchers at The University of Texas MD Anderson Cancer Center report in the journal Cell Reports.

"Prolactin is a potent growth factor for many types of cancers, including ovarian cancer," said senior author Anil Sood, M.D., professor of Gynecologic Oncology and Reproductive Medicine. "When we block prolactin signaling, it sets off a chain of downstream events that result in cell death by autophagy."

Autophagy – self-eating – is a natural cellular defense against lack of nutrients and other stressors. It also recycles damaged organelles and proteins for new use by the cell. Autophagy puts the cell in an inactive quiet state called quiescence, which allows it to recover, Sood said. For cancer cells, it's a way to survive treatment.

"Our findings provide a clinical rationale for blocking prolactin and its receptor and for using prolonged autophagy as an alternative strategy for treating cancers," said Yunfei Wen, Ph.D., first author of this study and instructor of Gynecologic Oncology.

Steep reductions in tumor weight for mice with ovarian cancer

Prolactin (PRL) is a hormone previously implicated in ovarian, endometrial and other cancer development and progression. When PRL binds to its cell membrane receptor, PRLR, activation of cancer-promoting cell signaling pathways follows. Poor understanding of the underlying processes has made the pathway hard to target for cancer treatment, Sood said.

Given that knowledge, the researchers started with mouse experiments and worked backward to cell line experiments, a reversal of the usual order of preclinical cancer research.

A slight variant of normal prolactin called G129R interferes with the connection between prolactin and its receptor. Using G129R, Sood and colleagues treated mice that had two different lines of human ovarian cancer that each expresses the prolactin receptor.

After 28 days of treatment with G129R, tumor weights fell by 50 percent for mice with either type of ovarian cancer. Adding the taxane-based chemotherapy agent paclitaxel, commonly used to treat ovarian cancer, cut tumor weight by 90 percent. Higher doses of G129R may result in even greater therapeutic benefit, Sood said.

The mice did not otherwise lose weight, suffer lowered blood counts or show any other sign of toxicity of side effects from G129R treatment in the liver, spleen or kidneys.

3D experiments show death by self-eating

The team used three-dimensional culture of cancer spheroids, where treatment with the prolactin-mimicking peptide sharply reduced the number of spheroids. Treatment also blocked the activation of JAK2 and STAT signaling pathways known to promote cancer.

Protein analysis in the treated spheroids showed increased presence of autophagy factors and genomic analysis revealed increased expression of a number of genes involved in autophagy progression and cell death.

A series of experiments using fluorescence and electron microscopy showed that the cytosol of treated cells had large numbers of cavities caused by autophagy, a hallmark of autophagy-induced cell death.

Autophagy works by encasing targeted proteins or organelles in a membrane, which then connects with lysosomes that dissolve the contents, leaving empty cavities, or vacuoles. Adding an autophagy inhibitor reversed the treatment effect of G129R in the 3D spheres.

Connection to ovarian cancer patient survival

The team also connected the G129R-induced autophagy to the activity of PEA-15, a known cancer inhibitor. Analysis of tumor samples from 32 ovarian cancer patients showed that tumors express higher levels of the prolactin receptor and lower levels of phosphorylated PEA-15 than normal ovarian tissue.

Patients with low levels of the prolactin receptor and higher PEA-15 had longer overall survival than those with high PRLR and low PEA-15.

###

The researchers are working to take G129R to clinical trials said Sood, who holds the Bettyann Asche Murray Distinguished Professorship in Ovarian Cancer Research.

Co-authors with Wen and Sood are Behrouz Zand, M.D., Chunhua Lu, M.D., Ph.D., Amy Carroll, M.D., Yu Kang, M.D., Ph.D., Rajesha Rupaimoole, Heather Dalton, M.D., and Robert Coleman, M.D., of Gynecologic Oncology and Reproductive Medicine; Bulent Ozpolat, M.D., Ph.D., Erkan Yuca, Ph.D., Neslihan Alpay, Ph.D., Ibrahim Tekedereli, M.D., Walter Hittelman, Ph.D., and Gabriel Lopez-Berestein

Scott Merville | EurekAlert!

Further reports about: Cancer Gynecologic Oncology autophagy death ovarian prolactin receptor

More articles from Life Sciences:

nachricht Protein Shake-Up
27.03.2015 | Oak Ridge National Laboratory

nachricht How did the chicken cross the sea?
27.03.2015 | Michigan State University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Experiment Provides the Best Look Yet at 'Warm Dense Matter' at Cores of Giant Planets

In an experiment at the Department of Energy's SLAC National Accelerator Laboratory, scientists precisely measured the temperature and structure of aluminum as...

Im Focus: Energy-autonomous and wireless monitoring protects marine gearboxes

The IPH presents a solution at HANNOVER MESSE 2015 to make ship traffic more reliable while decreasing the maintenance costs at the same time. In cooperation with project partners, the research institute from Hannover, Germany, has developed a sensor system which continuously monitors the condition of the marine gearbox, thus preventing breakdowns. Special feature: the monitoring system works wirelessly and energy-autonomously. The required electrical power is generated where it is needed – directly at the sensor.

As well as cars need to be certified regularly (in Germany by the TÜV – Technical Inspection Association), ships need to be inspected – if the powertrain stops...

Im Focus: 3-D satellite, GPS earthquake maps isolate impacts in real time

Method produced by UI researcher could improve reaction time to deadly, expensive quakes

When an earthquake hits, the faster first responders can get to an impacted area, the more likely infrastructure--and lives--can be saved.

Im Focus: Atlantic Ocean overturning found to slow down already today

The Atlantic overturning is one of Earth’s most important heat transport systems, pumping warm water northwards and cold water southwards. Also known as the Gulf Stream system, it is responsible for the mild climate in northwestern Europe. 

Scientists now found evidence for a slowdown of the overturning – multiple lines of observation suggest that in recent decades, the current system has been...

Im Focus: Robot inspects concrete garage floors and bridge roadways for damage

Because they are regularly subjected to heavy vehicle traffic, emissions, moisture and salt, above- and underground parking garages, as well as bridges, frequently experience large areas of corrosion. Most inspection systems to date have only been capable of inspecting smaller surface areas.

From April 13 to April 17 at the Hannover Messe (hall 2, exhibit booth C16), engineers from the Fraunhofer Institute for Nondestructive Testing IZFP will be...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

World Conference On Regenerative Medicine 2015: Registration And Abstract Submission Now Open

25.03.2015 | Event News

University presidents from all over the world meet in Hamburg

19.03.2015 | Event News

10. CeBiTec Symposium zum Big Data-Problem

17.03.2015 | Event News

 
Latest News

Two Most Destructive Termite Species Forming Superswarms in South Florida

27.03.2015 | Agricultural and Forestry Science

ORNL-Led Team Demonstrates Desalination with Nanoporous Graphene Membrane

27.03.2015 | Materials Sciences

Coorong Fish Hedge Their Bets for Survival

27.03.2015 | Ecology, The Environment and Conservation

VideoLinks
B2B-VideoLinks
More VideoLinks >>>