Interrupting protein signal forces cancer to self-destruct

Preclinical research has found that inhibiting protein signals causes unconventional cell death. When some cancer cells undergo chemotherapy or radiation they manage to stay alive by consuming a part of themselves, essentially allowing them to sleep through the treatment and then reawake as a tougher, more resistant, disease.

However, by interfering with a single cancer-promoting protein - prolactin (PRL) - and its receptor, this defence mechanism can be manipulated into self-cannibalisation, according to researchers at The University of Texas MD Anderson Cancer Center.

According to the study, published in the Cell Reports journal, self-eating or autophagy is a common cellular defense to protect itself against a lack of nutrients and other stressors. This puts the cell in an inactive state called quiescence, which allows it to recover and recycle damaged parts, according to the researchers.

"Prolactin is a potent growth factor for many types of cancers, including ovarian cancer," said senior author Anil Sood, 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."

The researchers said that this study could lead to more studies into alternative treatments for cancer.

PRL is a hormone that has been linked to the development of ovarian cancer. When it connects with its cell membrane receptor, PRLR, this leads to activation of cancer-promoting cell signaling pathways. However, according to Professor Sood, a lack of understanding in the underlying processes has made the pathway hard to target for cancer treatment.

The researchers initially experimented with mice and then worked back to cell line experiments, in contrast to the usual order of preclinical cancer research. A variant of PRL - G129R -  interferes with the connection between prolactin and its receptor. Using G129R, the team of researchers treated mice that had two different lines of human ovarian cancer, which each expressing the prolactin receptor.

After 28 days of G129R treatment, tumour weights fell by 50 per cent for mice with both types of ovarian cancer. When this was combined with taxane-based chemotherapy agent paclitaxel, which is often used to treat ovarian cancer, tumour weight was reduced by 90 per cent. 

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.