Featured Research

from universities, journals, and other organizations

Jamming a protein signal forces cancer cells to devour themselves

Date:
April 3, 2014
Source:
University of Texas M. D. Anderson Cancer Center
Summary:
Inhibiting cancer-promoting prolactin causes unconventional cell death in preclinical research, a study shows. "Prolactin is a potent growth factor for many types of cancers, including ovarian cancer," said the study's senior author. "When we block prolactin signaling, it sets off a chain of downstream events that result in cell death by autophagy."

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.


Story Source:

The above story is based on materials provided by University of Texas M. D. Anderson Cancer Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. Yunfei Wen, Behrouz Zand, Bulent Ozpolat, MiroslawJ. Szczepanski, Chunhua Lu, Erkan Yuca, AmyR. Carroll, Neslihan Alpay, Chandra Bartholomeusz, Ibrahim Tekedereli, Yu Kang, Rajesha Rupaimoole, ChadV. Pecot, HeatherJ. Dalton, Anadulce Hernandez, Anna Lokshin, SusanK. Lutgendorf, Jinsong Liu, WalterN. Hittelman, WenY. Chen, Gabriel Lopez-Berestein, Marta Szajnik, NaotoT. Ueno, RobertL. Coleman, AnilK. Sood. Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death. Cell Reports, 2014; DOI: 10.1016/j.celrep.2014.03.009

Cite This Page:

University of Texas M. D. Anderson Cancer Center. "Jamming a protein signal forces cancer cells to devour themselves." ScienceDaily. ScienceDaily, 3 April 2014. <www.sciencedaily.com/releases/2014/04/140403131738.htm>.
University of Texas M. D. Anderson Cancer Center. (2014, April 3). Jamming a protein signal forces cancer cells to devour themselves. ScienceDaily. Retrieved July 22, 2014 from www.sciencedaily.com/releases/2014/04/140403131738.htm
University of Texas M. D. Anderson Cancer Center. "Jamming a protein signal forces cancer cells to devour themselves." ScienceDaily. www.sciencedaily.com/releases/2014/04/140403131738.htm (accessed July 22, 2014).

Share This




More Health & Medicine News

Tuesday, July 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Courts Conflicted Over Healthcare Law

Courts Conflicted Over Healthcare Law

AP (July 22, 2014) Two federal appeals courts issued conflicting rulings Tuesday on the legality of the federally-run healthcare exchange that operates in 36 states. (July 22) Video provided by AP
Powered by NewsLook.com
Why Do People Believe We Only Use 10 Percent Of Our Brains?

Why Do People Believe We Only Use 10 Percent Of Our Brains?

Newsy (July 22, 2014) The new sci-fi thriller "Lucy" is making people question whether we really use all our brainpower. But, as scientists have insisted for years, we do. Video provided by Newsy
Powered by NewsLook.com
Scientists Find New Way To Make Human Platelets

Scientists Find New Way To Make Human Platelets

Newsy (July 22, 2014) Boston scientists have discovered a new way to create fully functioning human platelets using a bioreactor and human stem cells. Video provided by Newsy
Powered by NewsLook.com
Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

TheStreet (July 21, 2014) New research shows Gilead Science's drug Sovaldi helps in curing hepatitis C in those who suffer from HIV. In a medical study, the combination of Gilead's Hep C drug with anti-viral drug Ribavirin cured 76% of HIV-positive patients suffering from the most common hepatitis C strain. Hepatitis C and related complications have been a top cause of death in HIV-positive patients. Typical medication used to treat the disease, including interferon proteins, tended to react badly with HIV drugs. However, Sovaldi's %1,000-a-pill price tag could limit the number of patients able to access the treatment. TheStreet's Keris Lahiff reports from New York. Video provided by TheStreet
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:
from the past week

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