Jamming a protein signal forces cancer cells to devour themselves

April 3, 2014, University of Texas M. D. Anderson Cancer Center

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 ," 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 by ."

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 , 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 , 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 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.

Explore further: Autophagy predicts which cancer cells live and die when faced with anti-cancer drugs

Related Stories

Autophagy predicts which cancer cells live and die when faced with anti-cancer drugs

January 10, 2014
(Medical Xpress)—When a tumor is treated with an anti-cancer drug, some cells die and, unfortunately, some cells tend to live. A University of Colorado Cancer Center study published in the journal Nature Cell Biology details ...

Blocking autophagy with malaria drug may help overcome resistance to melanoma BRAF drugs

February 24, 2014
Half of melanoma patients with the BRAF mutation have a positive response to treatment with BRAF inhibitors, but nearly all of those patients develop resistance to the drugs and experience disease progression.

Resistance is futile: Researchers identify gene that mediates cisplatin resistance in ovarian cancer

April 15, 2013
Platinum compounds, such as cisplatin and carboplatin, induce DNA cross-linking, prohibiting DNA synthesis and repair in rapidly dividing cells. They are first line therapeutics in the treatment of many solid tumors, but ...

Researchers discover protein to better forecast prognosis of prostate cancer patients

February 17, 2014
(Medical Xpress)—Researchers at the Texas A&M Health Science Center (TAMHSC) Institute of Biosciences and Technology in Houston have identified a biomarker that will aid in more accurately determining the prognosis for ...

Acidic tumour pH inhibits drug effect

February 11, 2014
Low pH in tumours counteracts the desired effect of the drug chloroquine, according to a new study from Karolinska Institutet in Sweden. The results, which are published in the journal Autophagy, might explain possible lack ...

Recommended for you

Boosting cancer therapy with cross-dressed immune cells

January 22, 2018
Researchers at EPFL have created artificial molecules that can help the immune system to recognize and attack cancer tumors. The study is published in Nature Methods.

Workouts may boost life span after breast cancer

January 22, 2018
(HealthDay)—Longer survival after breast cancer may be as simple as staying fit, new research shows.

Cancer patients who tell their life story find more peace, less depression

January 22, 2018
Fifteen years ago, University of Wisconsin–Madison researcher Meg Wise began interviewing cancer patients nearing the end of life about how they were living with their diagnosis. She was surprised to find that many asked ...

Single blood test screens for eight cancer types

January 18, 2018
Johns Hopkins Kimmel Cancer Center researchers developed a single blood test that screens for eight common cancer types and helps identify the location of the cancer.

Researchers find a way to 'starve' cancer

January 18, 2018
Researchers at Vanderbilt University Medical Center (VUMC) have demonstrated for the first time that it is possible to starve a tumor and stop its growth with a newly discovered small compound that blocks uptake of the vital ...

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.