Scientists curb growth of cancer cells by blocking access to key nutrients

January 10, 2018, Salk Institute
Credit: CC0 Public Domain

Salk researchers have discovered how to curb the growth of cancer cells by blocking the cells' access to certain nutrients. The approach, detailed in a new paper published today in Nature, took advantage of knowledge on how healthy cells use a 24-hour cycle to regulate the production of nutrients and was tested on glioblastoma brain tumors in mice.

"When we block access to these resources, cancer cells starve to death but normal cells are already used to this constraint so they're not affected," says Satchidananda Panda, a professor in the Salk Institute's Regulatory Biology Laboratory and lead author of the paper.

The circadian cycle, the intrinsic clock that exists in all living things, is known to help control when individual cells produce and use nutrients, among many other functions. Scientists previously discovered that proteins known as REV-ERBα and REV-ERBβ are responsible for turning on and off cells' ability to synthesize fats, as well as their ability to recycle materials—a process called autophagy—throughout the day. In healthy cells, fat synthesis and autophagy are allowed to occur for about 12 hours a day when REV-ERB protein levels remain low. The rest of the time, higher levels of the REV-ERB proteins block the processes so that the cells are not flooded with excessive fat synthesis and recycled nutrients. In the past, researchers developed compounds to activate REV-ERBs in the hopes of stopping fat synthesis to treat certain metabolic diseases.

Panda and his colleagues wondered whether activating REV-ERBs would slow cancer growth, since cancer cells heavily rely on the products of both fat synthesis and autophagy to grow.

"While current cancer research was investigating established cancer hallmarks/characteristic we decided to explore something completely new," says Research Associate Gabriele Sulli, the paper's first and co-corresponding author. "Given the importance of the circadian clock in the regulation of many cellular and physiological processes we hypothesize that targeting the circadian clock with drugs may open the way to novel anticancer strategies. This study is very exciting because it sheds light on a new uncharacterized way to treat cancer with very limited toxicity."

Adds Panda, "We've always thought about ways to stop cancer cells from dividing. But once they divide, they also have to grow before they can divide again, and to grow they need all these raw materials that are normally in short supply. So cancer cells devise strategies to escape the daily constraints of the circadian clock."

Salk researchers discover how to curb the growth of cancer cells by activating their biological clocks. Credit: Salk Institute

Although cancer cells contain REV-ERB proteins, somehow they remain inactive. Panda's team used two REV-ERB activators that had already been developed—SR9009 and SR9011—in studies on a variety of cancer cells, including those from T cell leukemia, breast cancer, colorectal cancer, melanoma and glioblastoma. In each cell line, treatment with the REV-ERB activators was enough to kill the cells. The same treatment on healthy cells had no effect. "Activating REV-ERBs seemed to work in all the types of cancer we tried," says Panda. "That makes sense because irrespective of where or how a cancer started, all cancer cells need more nutrients and more recycled materials to build new cells."

Panda then went on to test the drugs on a new mouse model of glioblastoma recently developed by Inder Verma, a professor in the Salk Institute's Laboratory of Genetics. Once again, the REV-ERB activators were successful at killing cancer cells and stopping tumor growth but seemed not to affect the rest of the mice's cells. Verma says the findings are not only exciting because they point toward existing REV-ERB activators as potential cancer drugs, but also because they help shine light on the importance of the link between the circadian cycle, metabolism and cancer.

"These are all fundamental elements required by all living cells," says Verma. "By affecting REV-ERBs, you get to the heart of how cells grow and proliferate, but there are lots of other ways to get at this as well."

Verma says his group is planning follow-up studies on how, exactly, the REV-ERB activators alter metabolism, as well as whether they may affect the metabolism of bacteria in the microbiome, the collection of microbes that live in the gut. Panda's team is hoping to study the role of other circadian cycle genes and proteins in cancer.

Panda, Verma and coauthor Alan Saghatelian, also a Salk professor, are all members of the Salk Cancer Center, a National Cancer Institute–designated basic research cancer center.

Other researchers on the study were Amy Rommel and Matthew J. Kolar of the Salk Institute; Xiaojie Wang and Maksim V. Plikus of the University of California, Irvine; and Francesca Puca of The University of Texas MD Anderson Cancer Center.

Explore further: Cancer overrides the circadian clock to survive

More information: Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence, Nature (2018). nature.com/articles/doi:10.1038/nature25170

Related Stories

Cancer overrides the circadian clock to survive

December 28, 2017
Tumor cells use the unfolded protein response to alter circadian rhythm, which contributes to more tumor growth, Hollings Cancer Center researchers at the Medical University of South Carolina (MUSC) find. A key part of the ...

Time matters: Does our biological clock keep cancer at bay?

December 7, 2017
Our body has an internal biological or "circadian" clock, which cycles daily and is synchronized with solar time. New research done in mice suggests that it can help suppress cancer. The study, publishing 7 December in the ...

Mitochondria drive cell survival in times of need

September 21, 2017
McGill University researchers have discovered a mechanism through which mitochondria, the energy factory of our body's cells, play a role in preventing cells from dying when the cells are deprived of nutrients - a finding ...

New study reveals breast cancer cells recycle their own ammonia waste as fuel

October 19, 2017
Breast cancer cells recycle ammonia, a waste byproduct of cell metabolism, and use it as a source of nitrogen to fuel tumor growth, report scientists from Harvard Medical School in the journal Science.

Cancer cells grow by exploiting their neighbours

January 25, 2017
Researchers at the University of Oslo and Oslo University Hospital have discovered that cancer cells grow by stealing energy from neighbouring cells.

Identification of PTPRZ as a drug target for cancer stem cells in glioblastoma

July 19, 2017
Glioblastoma is a malignant brain tumor with high mortality. Cancer stem cells are thought to be crucial for tumor initiation and its recurrence after standard therapy with radiation and temozolomide (TMZ) chemotherapy. Protein ...

Recommended for you

Research shows possible new target for immunotherapy for solid tumors

April 24, 2018
Research from the University of Cincinnati (UC) reveals a potential new target to help T cells (white blood cells) infiltrate certain solid tumors.

Changes in breast tissue increase cancer risk for older women

April 24, 2018
Researchers in Norway, Switzerland, and the United States have identified age-related differences in breast tissue that contribute to older women's increased risk of developing breast cancer. The findings, published April ...

Targeting molecules called miR-200s and ADAR2 could prevent tumor metastasis in patients with colorectal cancer

April 24, 2018
Colorectal cancer is the third most common cancer worldwide and the third-leading cause of cancer-related deaths. The main cause of death in patients with colorectal cancer is liver metastasis, with nearly 70% of patients ...

Experimental arthritis drug prevents stem cell transplant complication

April 24, 2018
An investigational drug in clinical trials for rheumatoid arthritis prevents a common, life-threatening side effect of stem cell transplants, new research from Washington University School of Medicine in St. Louis shows. ...

Scientists develop a new model for glioblastoma using gene-edited organoids

April 24, 2018
Glioblastoma multiforme (GBM) is an incredibly deadly brain cancer and presents a serious black box challenge. It's virtually impossible to observe how these tumors operate in their natural environment and animal models don't ...

Technology used to map Mars now measuring effect of treatment on tumours

April 24, 2018
A machine learning approach for assessing images of the craters and dunes of Mars, which was developed at The University of Manchester, has now been adapted to help scientists measure the effects of treatments on tumours.

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.